Respiratory Medicine

Series Editor:
Sharon I.S. Rounds

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M. Safwan Badr
Editor

Essentials of Sleep Medicine

An Approach for Clinical Pulmonology
Editor
M. Safwan Badr, MD
Department of Internal Medicine
Harper University Hospital
Wayne State University School of Medicine
Detroit, MI, USA
[email protected]

ISBN 978-1-60761-734-1 e-ISBN 978-1-60761-735-8

DOI 10.1007/978-1-60761-735-8
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Preface

Sleep has fascinated poets, lovers and philosophers since time immemorial. It was a
metaphor for rest, rejuvenation and restoration. Physicians viewed sleep and thought
of sleep as a “safe harbor” keeping illness away, and as a cuddly “teddy bear” giving
warmth and serenity. Few physicians appreciated sleep complexity beyond the
elemental aspects; patients need rest and sleep. Disorders of sleep were the subject
of interesting discussions at teaching conferences but the only condition worthy of
discussion was lack of sleep, and it was often due to tension or anxiety.
The image of sleep as a quiescent period changed dramatically when scientists
began to uncover the mysteries of sleep: the good, the bad and the ugly! The discovery
of REM sleep altered the popular image and revealed a fascinating constellation of
active processes throughout the body. However, it was sleep apnea that propelled
sleep into mainstream medicine. This is a condition where sleep is anything but rest.
We learned that sleep can be seen as a “grizzly bear” as we discovered that sleep
apnea has significant adverse consequences and may contribute to mortality and to
traffic fatalities.
The initial phase of sleep medicine was marked by different specialties providing
care for conditions deemed within their domain. Neurologists, psychiatrists and pul-
monologists focused on different disorders and different approaches to diagnosis
and treatment. Fortunately, we soon discovered that sleep is an interdisciplinary
field, transcending traditional, system-based specialties. Patients present with com-
plaints and not diagnoses, and sleep disorders share a small number of sleep-related
complaints. We learned that snoring may represent a serious condition, that daytime
sleepiness is not a sign of narcolepsy per se, and that insomnia is not necessarily due
to anxiety or depression. Therefore, physicians who care for any sleep disorder must
learn about all sleep disorders.
The focus of this book is practical; relevant facts help the busy practicing physi-
cians provide better care for sleep disorders as part of a comprehensive care. It is
entitled “for the pulmonologist” but can equally benefit internists, neurologists, psy-
chiatrists and family physicians. Residents and fellows may find the focused descrip-
tion and practical approach beneficial. One specific focus is the notion that most

v
vi Preface

clinical conditions interact with sleep, many medications affect sleep and some are
aggravated by sleep.
This book represents the collective effort of a team of professionals. Each chapter
was written by an expert in the field blending seasoned experts with emerging leaders.
Editing a book is a challenging process as one tries to keep a group of busy and
forgetful academicians on schedule. I am grateful to Amanda Quinn and Joni Fraser
of Springer for their support, guidance, and superb organizational skills. I would
like to thank Springer Science and Business Media for supporting this project.

Detroit, MI M. Safwan Badr

Contents

1 Normal Sleep .......................................................................................... 1

James A. Rowley and M. Safwan Badr
2 Pharmacology of Sleep .......................................................................... 17
Susmita Chowdhuri
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography
and Portable Monitors ........................................................................... 55
Chunbai Zhang, Stefanos N. Kales, and Atul Malhotra
4 Approach to Hypersomnia .................................................................... 73
James A. Rowley
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea ................... 91
Jessie P. Bakker, Atul Malhotra, and Sanjay R. Patel
6 Obstructive Sleep Apnea: Clinical Features and Adverse
Consequences.......................................................................................... 115
Geraldo Lorenzi-Filho and Pedro Rodrigues Genta
7 Assessments of Driving Risk in Sleep Apnea ....................................... 129
Kingman P. Strohl
8 Nasal Continuous Positive Airway Pressure (CPAP)
Treatment ................................................................................................ 143
Srinivas Bhadriraju and Nancy Collop
9 Obstructive Sleep Apnea: Oral Appliances ......................................... 155
Peter A. Cistulli, Kate Sutherland, and Andrew S.L. Chan
10 Obstructive Sleep Apnea: Surgery ....................................................... 175
Ryan J. Soose and Patrick J. Strollo
11 Sleep and Lung Disease ......................................................................... 203
Charles W. Atwood, Jr.

vii
viii Contents

12 Central Sleep Apnea .............................................................................. 219

M. Safwan Badr
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity............. 233
Clare E. Gargaro, Thomas Roth, and Christopher L. Drake
14 Management of Insomnia ...................................................................... 249
Luisa Bazan, Thomas Roth, and Christopher L. Drake
15 Circadian Disorders ............................................................................... 277
Brandon S. Lu, Jeff Kwon, and Phyllis C. Zee
16 Narcolepsy and Idiopathic Hypersomnia ............................................ 297
Imran Ahmed and Michael Thorpy
17 Parasomnias............................................................................................ 315
Hrayr Attarian
18 Movement Disorders .............................................................................. 349
Nidhi S. Undevia
19 Perioperative Care of Patients with Obstructive Sleep
Apnea Syndrome .................................................................................... 371
Haven R. Malish and Peter C. Gay
20 Sleep and Critical Illness ....................................................................... 395
Nimesh Patel and Sairam Parthasarathy

Index ................................................................................................................ 407

Contributors

Imran Ahmed, MD Sleep-Wake Disorders Center, Montefiore Medical Center,

Bronx, NY, USA
Hrayr Attarian, MD Northwestern University Feinberg School of Medicine,
Department of Neurology, Chicago, IL, USA
Charles W. Atwood, Jr., MD Sleep Disorders Program, Pulmonary and Sleep
Section, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
M. Safwan Badr, MD Department of Internal Medicine, Division of Pulmonary,
Critical Care and Sleep Medicine, Wayne State University School of Medicine,
Harper University Hospital, Detroit, MI, USA
Jessie P. Bakker, BSc, MSc, Ph.D Department of Medicine, University of Otago,
Wellington, New Zealand
Luisa Bazan, MD Sleep Disorders and Research Center, Henry Ford Hospital,
Detroit, MI, USA
Srinivas Bhadriraju, MD Pulmonary/Sleep Medicine, Emory University School
of Medicine, Atlanta, GA, USA
Andrew S.L. Chan, MBBS, Ph.D, FRACP, FCCP Department of Respiratory
Medicine, Centre for Sleep Health and Research, Royal North Shore Hospital,
St. Leonards, NSW, Australia
Susmita Chowdhuri, MD, MS Sleep Medicine Section, Medical Service,
John D. Dingell VA Medical Center and Wayne State University, Detroit,
MI, USA
Peter A. Cistulli, MBBS, Ph.D, MBA, FRACP, FCCP Department of Respiratory
Medicine, Centre for Sleep Health and Research, Royal North Shore Hospital,
St. Leonards, NSW, Australia
Nancy Collop, MD Emory Sleep Center, Emory University, Atlanta,
GA, USA

ix
x Contributors

Christopher L. Drake, Ph.D Sleep Disorders and Research Center,

Henry Ford Hospital, Detroit, MI, USA
Clare E. Gargaro, BS Department of Sleep Medicine, Henry Ford Hospital,
Detroit, MI, USA
Peter C. Gay, MD Department of Medicine, Mayo Clinic, Rochester, MN, USA
Pedro Rodrigues Genta, MD Pulmonary Division, Heart Institute (InCor),
University of São Paulo School of Medicine, São Paulo, Brazil
Stefanos N. Kales, MD, MPH Division of Sleep Medicine,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Jeff Kwon, MD Division of Pulmonary, Critical Care, and Sleep Medicine,
Bridgeport Hospital, Bridgeport, CT, USA
Geraldo Lorenzi-Filho, Ph.D, MD Pulmonary Division, Heart Institute (InCor),
University of São Paulo School of Medicine, São Paulo, Brazil
Brandon S. Lu, MD, MS Department of Medicine, California Pacific
Medical Center, San Francisco, CA, USA
Atul Malhotra, MD Sleep Disorders Program, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
Haven R. Malish, MD Sleep Medicine, Mayo Clinic, Rochester, MN, USA
Sairam Parthasarathy, MD Research Service Line, Southern Arizona
VA Health Care System, Tucson, AZ, USA
Nimesh Patel, DO Department of Medicine, Section of Pulmonary,
Critical Care, and Sleep Medicine, University of Arizona, Tucson, AZ, USA
Sanjay R. Patel, MD, MS Division of Sleep Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
Thomas Roth, Ph.D Sleep Disorders and Research Center, Henry Ford Hospital,
Detroit, MI, USA
James A. Rowley, MD Department of Internal Medicine, Division of Pulmonary,
Critical Care and Sleep Medicine, Wayne State University School of Medicine,
Harper University Hospital, Detroit, MI, USA
Ryan J. Soose, MD Division of Sleep Surgery, Department of Otolaryngology,
University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Kingman P. Strohl, MD Louis Stokes Cleveland DVA Medical Center,
Cleveland, OH, USA
Patrick J. Strollo, MD Division of Pulmonary, Allergy and Critical Care Medicine,
UPMC Sleep Medicine Center, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA
Contributors xi

Kate Sutherland, Ph.D Department of Respiratory Medicine, Centre for Sleep

Health and Research, Royal North Shore Hospital, St. Leonards, NSW, Australia
Michael Thorpy, MD Sleep-Wake Disorders Center, Montefiore Medical Center,
Bronx, NY, USA
Nidhi S. Undevia, MD Department of Medicine, Division of Pulmonary
and Critical Care Medicine, Loyola Center for Sleep Disorders, Loyola University
Medical Center, Maywood, IL, USA
Phyllis C. Zee, MD, Ph.D Department of Neurology, Sleep Disorders Center,
Northwestern University, Chicago, IL, USA
Chunbai Zhang, MD, MPH Division of Sleep Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
Chapter 1
Normal Sleep

James A. Rowley and M. Safwan Badr

Keywords NREM sleep • REM sleep • EEG • Upper airway resistance • Hypocapnic
apneic threshold • Critical closing pressure (Pcrit) • Heart rate variability • Esophageal
sphincter

Normal Sleep Stages and Architecture

Normal human sleep is generally divided into four stages. Consensus definitions for
the visual scoring of sleep were published in 2007 and the reader is referred to the
American Academy of Sleep Medicine Scoring Manual for full definitions and
criteria for the scoring of sleep on polysomnograms [1, 2]. The following will
provide a brief overview of the electroencephalographic (EEG) characteristics of
the different sleep stages (Fig. 1.1).
Full wakefulness is characterized by mixed-frequency, low amplitude EEG
activity, often in association with high chin muscle tone, eye blinks, and rapid eye
movements. As the patient transitions to sleep with eyes closed, wakefulness is
characterized by a 8–13-Hz sinusoidal activity called alpha sleep. Alpha sleep is
best recorded over the occipital region and is attenuated by eye opening.
Nonrapid eye movement (NREM) sleep composes the majority of the night and
is characterized by the predominance of homeostatic mechanisms for breathing,
cardiovascular and gastrointestinal function, and normal thermoregulation. NREM
sleep is divided into three stages. N1 sleep is a transitional period during which the
individual still usually has some awareness of his/her environment. N1 sleep is
characterized by a slowing of the background wake EEG frequencies with a

J.A. Rowley (*) • M.S. Badr

Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine,
Wayne State University School of Medicine, Harper University Hospital, Detroit, MI, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 1
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_1,
© Springer Science+Business Media, LLC 2012
Fig. 1.1 Representative 30-s epochs of sleep stages. (a) Wakefulness with alpha rhythm; (b) stage
N1; (c): stage N2 with K-complex and spindle; (d) stage N3 (slow wave sleep); and (e) stage R.
For all epochs: E1-M2: left electro-oculogram; E2-M2: right electro-oculogram; chin 2: chin
EMG; F4-M1: right frontal EEG; C4-M1: right central EEG; O2-M1: right occipital EEG
1 Normal Sleep 3

Fig. 1.2 Representative hypnogram showing normal sleep architecture

predominance of low amplitude activity in 4–7 Hz (often referred to as theta activity).

Slow eye movements are commonly observed during N1 sleep. N2 sleep, at which
time the individual generally is no longer aware of his/her environment, is charac-
terized by the appearance of sleep spindles and K complexes superimposed on a
background of theta activity. Sleep spindles are rhythmic sinusoidal waves of
12–14 Hz, usually best recorded on central EEG leads. K complexes are diphasic
waves having a well-delineated sharp negative component followed by a slow posi-
tive component. N3 sleep, commonly known as slow wave sleep, is scored when
slow wave activity is recorded on >20% of an epoch. By definition, slow waves are
of low frequency (generally 0.5–2 Hz) and have large amplitude (>75 mV).
As opposed to NREM sleep, rapid eye movement (REM or Stage R) is character-
ized by variations and instability in cardiopulmonary function and instability of
body temperature control. In addition, Stage R is characterized by dreaming, relative
atonia of all muscle groups except the diaphragm and in men, erections. On EEG,
Stage R is characterized by a low amplitude, mixed frequency EEG, similar to that
seen in Stage N1 sleep. In addition, Stage R is characterized by the presence of
REMs and decreased chin muscle tone. Stage R is a unique time of the night in that
dreaming occurs during Stage R sleep.
Sleep architecture describes the organization of the sleep stages over the course of
the night (Fig. 1.2). The normal sleep cycle in a young adult (generally considered
the standard) begins with transitioning from wakefulness to N1 sleep and then quickly
transitioning to N2 and N3 sleep. The first occurrence of Stage R sleep is generally
at about 90 min and individuals then cycle between NREM and REM sleep every
90–110 min throughout the night. In general, N3 sleep predominates in the first half
of the night whereas Stage R predominates in the second half of the night. For an
average individual in their second decade, Stage N1 is 2–5% of the total sleep time,
Stage N2 is 45–55%, Stage N3 13–23%, and Stage R is 20–25% [3].
Overall sleep architecture is dependent upon stage of development and aging
(Fig. 1.3). For instance, infants generally spend up to 50% of the night in Stage R
sleep and often have a cycle of REM sleep prior to NREM sleep. In addition, the
4 J.A. Rowley and M.S. Badr

Fig. 1.3 Changes in sleep stages as a percentage of sleep time across the age span. WASO wake
after sleep onset; REM rapid eye movement sleep; SWS slow wave sleep. See text for details
(reprinted by permission from Ohayon et al. [3])

duration of the NREM–REM cycle is 60 min through most of childhood. Over the
span of time between young adulthood to elderly, there are changes in most sleep
stages, including decreased total sleep time and sleep efficiency, increased percentage
of Stages N1 and N2, decreased percentage of Stages N3 and R. These changes with
aging have been shown to be more prominent in men than women [3, 4].

Breathing During Sleep: Ventilation and the Upper Airway

Summary of Normal Breathing and Ventilation During Sleep

Ventilatory motor output during sleep decreases from its normal levels in wakefulness,
leading to decreased tidal volume and minute ventilation. The decreased ventilation
is accompanied by reduced upper-airway dilator muscle activity resulting in
decreased upper-airways caliber and increased airflow resistance. These biological
changes may account for the observed increase in Paco2 and decrease in Pao2 during
sleep, despite the diminished overall metabolic rate. A decrease in chemorespon-
siveness during sleep may also explain the increased Paco2. Overall, breathing
becomes more dependent on chemical stimuli, especially PaCO2.
1 Normal Sleep 5

In contrast to NREM sleep, REM sleep is characterized by variability in ventilation.

This variability consists of sudden changes in respiratory amplitude and frequency
associated with the periods of phasic REMs. Because of this variability, minute
ventilation in REM sleep has been shown to be the same, increased, or decreased
compared with NREM sleep. Upper-airway resistance has also been reported variably
as either the same or increased compared to wakefulness and NREM sleep. Finally,
hypercapnic and hypoxic ventilatory chemoresponsiveness is decreased in REM
sleep compared to wakefulness and possibly even NREM sleep.

Effect of Sleep on Control of Breathing

Chemoresponsiveness refers to changing ventilation in response to changes in

chemical stimuli. Chemosensitivity is influenced by changes in neural activity during
sleep. Thus, hypoxic and hypercapnic chemoresponsiveness contributes to maintaining
ventilation during sleep. Conversely, hypocapnia is a potent inhibitor of ventilation
during NREM sleep and is a key mechanism of central apnea [5].
The sleep state is characterized by decreased ventilatory response to hypercapnia
(HCVR) in human adults compared to wakefulness [6–12]. While the sensitivity to
Paco2 does not appear to differ within NREM sleep stages, the HCVR during REM
stage is depressed further compared with NREM sleep [6, 8]. Similarly, hypoxic
ventilatory responsiveness (HVR) is also diminished during NREM sleep compared
to wakefulness, with a further decrease in REM sleep [10, 13–15]. Nevertheless, the
effect of sleep on chemoresponsiveness is confounded by the sleep effect on upper
airway mechanics and associated decrease in ventilation.
The loss of wakefulness stimulus to breathe renders ventilation during NREM
sleep critically dependent on chemoreceptor stimuli (Pao2 and Paco2). Reduced
Paco2 is a powerful inhibitory factor of ventilation during sleep. Therefore, central
apnea develops when Paco2 is reduced below a highly reproducible hypocapnic
apneic threshold, unmasked by NREM sleep [5] (Fig. 1.4). Hypocapnia is probably
the most important inhibitory factor during NREM sleep. Hypocapnia, secondary to
hyperventilation, is key to the genesis of central sleep apnea in congestive heart
failure [16], and idiopathic central sleep apnea [17, 18], and may be relevant to the
pathogenesis of obstructive sleep apnea (OSA) as well [19–21].

Effect of Sleep on Upper-Airway Structure and Function

The sleep state is a challenge, rather than a rest period, for the ventilatory system.
Consequences of loss of wakefulness include reduced activity of upper-airway dila-
tors, reduced upper-airway caliber, increased upper-airway resistance, loss of load
compensation, and increased pharyngeal compliance and collapsibility. Ultimately,
these changes lead to reduced tidal volume and hypoventilation.
6 J.A. Rowley and M.S. Badr

Before mechanical During mechnaical After mechanical

ventilation ventilation ventilation
2
EEG -2
0
Flow (L/s) -0.2
300
VT (ml)
0
10
Psg (cmH2O) 6
44
PETCO2 (torr) 22
0
Pmask(cmH2O) 8
4
Δ PETCO2 =3 torr 5 sec.

Fig. 1.4 Induced hypocapnic central apnea during NREM sleep. Nasal mechanical ventilation
was used to decrease end-tidal Pco2 (PETco2). Cessation of mechanical ventilation caused central
apnea. Psg supraglottic pressure; Pmask mask pressure

The musculature of the upper airway consists of 24 pairs of striated muscles

extending from the nares to the larynx [22, 23]. There are at least ten muscles that
are classified as pharyngeal dilators. There are two patterns of electrical discharge
from these muscles: tonic (constant) activity, independent of phase of respiration,
and phasic activity, occurring during one part of the respiratory cycle. It is widely
accepted that upper-airway narrowing during sleep is due to a sleep-related decrease
in upper-airway muscle activity. During NREM sleep, available evidence indicates
a reduction in either the tonic or phasic activity for a variety of upper-airway mus-
cles [23], including the levator palatini [24], tensor palatini [25], palatoglossus [24],
and geniohyoid [26]. The effect of REM sleep on upper-airway muscle activity is
more compelling, with strong evidence that activity of phasic upper-airway dilating
muscles, such as the genioglossus, is greatly attenuated during REM sleep [27, 28],
particularly during periods of phasic REMs [29, 30].
The response of upper-airway muscle to chemical and mechanical perturbations
may be more relevant physiologically than reduced baseline activity. Pharyngeal
muscles display an attenuated response to negative pressure during NREM [31–33]
and REM sleep [34] compared to wakefulness. Similarly, responsiveness of the
genioglossus muscle to hypercapnia is also attenuated during sleep [35]. Decreased
responsiveness to challenges indicates that upper-airway muscles are less able to
maintain upper-airway patency in the face of chemical or mechanical perturbations.
The evidence for increased upper-airway resistance during sleep is compelling,
even in normal subjects [36–40]. The preponderance of evidence is that there are no
further increases in upper-airway resistance as subjects transition from NREM to
REM sleep [39–41]. However, it is important to note that upper-airway resistance
provides only a partial picture of the dynamic behavior of the pharyngeal airway
during sleep. Specifically, upper-airway resistance is generally expressed as a single
number representing the slope of pressure–flow relationship during inspiration. This
computation is predicated on a constant relationship between driving pressure and
inspiratory flow, which is true during normal breathing in normal subjects. However,
1 Normal Sleep 7

many subjects exhibit inspiratory-flow limitation, in which the pressure–flow graph

demonstrates a changing relationship culminating in complete dissociation between
pressure and flow (pressure continues to decrease with no further increase in flow).
While many authors equate increased upper airway resistance to increased collaps-
ibility, it is in reality a rather limited surrogate for susceptibility to pharyngeal
closure during sleep [42].
Using nasopharyngoscopy during naturally occurring sleep in normal subjects,
Rowley et al. have shown that pharyngeal cross-sectional area is decreased during
sleep at both the retropalatal and retroglossal levels [39, 40]. During NREM sleep,
both retropalatal cross-sectional area and retroglossal cross-sectional area decreased
to ~70% of the awake baseline cross-sectional area. The decreased cross-sectional
area is consistent with a decrease in upper-airway dilator activity with the onset of
NREM sleep. In REM sleep, retropalatal cross-sectional area did not decrease further
compared to NREM sleep [40]. In contrast, retroglossal cross-sectional area did
decrease further during REM compared to NREM sleep [39].
The ability of the ventilatory control system to compensate for changes in resistance
is essential for the preservation of alveolar ventilation. Increased resistance is an
example of resistive load, leading, during wakefulness, to increased effort to maintain
ventilation and Paco2. In contrast, hypoventilation occurs immediately upon imposing
a resistive load during NREM sleep, perhaps implying that loads are not perceived
during sleep [43]. Therefore, resistive loading results in decreased tidal volume and
minute ventilation and, hence, alveolar hypoventilation. The ensuing elevation of
arterial Paco2 restores ventilation toward normal levels. Teleologically, failure to
respond to loads preserves sleep continuity. The cost of allowing sleep continuity is
a mild elevation of Paco2. In fact, elevated Paco2 during sleep is one of few physi-
ologic situations where hypercapnia is tolerated.
The walls of the pharyngeal airway consist of compliant soft tissue structures,
amenable to changes in pressure during the respiratory cycle. During wakefulness,
upper-airway caliber is constant during inspiration, with a decreased caliber during
expiration, returning to inspiratory values at end-expiration. This finding has been
observed in both normal subjects [44, 45] and patients with sleep apnea [45] using
either computerized tomographic (CT) scanning or nasopharyngoscopy. Using
nasopharyngoscopy, NREM sleep was associated with significant dynamic within-
breath changes in cross-sectional area, reaching a nadir at midinspiration [45], with
a rapid increase in cross-sectional area during expiration [20].
The dynamic changes in upper-airway patency during sleep can be best investi-
gated using compliance as a measurement. Traditionally, compliance is the change
in volume for a given change in pressure. Compliance of the pharyngeal wall is an
important modulator of the effect of pressure changes on upper-airway patency.
Traditionally, upper-airway compliance has been measured in a static fashion by
measuring changes in cross-sectional area at different levels of pressure applied to
the upper airway [46–48]. Use of this technique has demonstrated that compliance
is increased as the pharyngeal caliber decreases [46, 47, 49]. In contrast, we have
combined measurement of cross-sectional area via fiberoptic nasopharyngoscopy
and measurement of intraluminal pressure at the same level during NREM and
8 J.A. Rowley and M.S. Badr

Fig. 1.5 Starling resistor model of the upper airway. In a starling resistor there is a collapsible
segment surrounded by an upstream and downstream noncollapsible segments. In this model, Pcrit
is assumed to be equal to the pressure surrounding airway. PUS upstream (nasopharyngeal) pres-
sure; PDS downstream (hypopharyngeal) pressure. In (a), both the PUS and PDS are greater than Pcrit,
the airway is wide open and flow will be proportional to the difference between PUS and PDS. In (b),
the Pcrit is greater than both PUS and PDS, the airway is closed, and there is no flow. In (c), PUS is
greater than Pcrit but Pcrit is greater than PDS, creating a condition of flow limitation; flow is propor-
tional to the difference between PUS and Pcrit

REM sleep. These studies have confirmed that retropalatal compliance is increased
during NREM sleep compared to wakefulness; in contrast, retropalatal compliance
during REM sleep is similar to that in wakefulness [40]. At the retroglossal level,
however, compliance was not increased during either NREM or REM sleep com-
pared to wakefulness [39]. Thus, pharyngeal compliance was not increased, despite
the known absence of upper-airway muscle activity during REM sleep.
Collapsibility refers to the propensity of the upper airway to collapse or obstruct
under certain conditions. While often used interchangeably with compliance, it differs
from compliance in that compliance measures the changes in upper-airway area for
given changes in pressure and not the propensity to collapse. Upper-airway collaps-
ibility has been primarily measured using the critical closing pressure or Pcrit.
Measurement of critical closing pressure or Pcrit is based upon the concept of the
Starling resistor (Fig. 1.5) [50]. In a Starling resistor, maximal flow through the resistor
is dependent upon the resistance of the segment upstream and the pressure surrounding
the collapsible segment. In normal subjects, the application of progressively negative
nasal pressure (upstream pressure) results in inspiratory-flow limitation, followed by
complete upper-airway obstruction [51]. Thus, this model of upper-airway mechanics
has several advantages as a method to study upper-airway collapsibility. First, it most
closely approximates the inspiratory-flow limitation that characterizes the breathing of
many subjects with snoring. Second, the model allows a functional approach to the
upper airway, which is key, given the complicated anatomy of the upper airway.
1 Normal Sleep 9

Applying this model to humans, it has been shown that across the spectrum of
sleep-disordered breathing, active Pcrit becomes progressively more positive, indicative
of increased propensity for airway collapse [51–53]. For instance, Pcrit in normal
subjects is generally <10 cmH2O while in patients with predominant hypopneas it is
between 0 and −5 cmH2O and in patients with predominant apneas it is >0 cmH2O.
Kirkness et al. found that in a group of 166 men and women with and without sleep
disordered breathing, passive Pcrit is higher in men and increases with increasing age
and BMI [54]. In addition, in these studies sleep apnea was largely absent in subjects
with a passive or active Pcrit more negative than −5 cmH2O [54, 55].

Cardiovascular Function During Sleep

NREM sleep is characterized by autonomic stability, driven by increased vagal

nerve activity and parasympathetic tone when compared to wakefulness. The
increased vagal activity results in an overall decrease in heart rate during NREM
sleep and frequent sinus arrhythmia coupled to respiratory variation. In sinus
arrhythmia, there is an increase in heart rate during inspiration to accommodate
increased venous return with a decrease in heart rate during expiration. Because of
the increased vagal tone, NREM sleep is associated with an increase in heart rate
variability compared to wakefulness [56, 57]. In addition, NREM sleep is associated
with a decrease in cardiac output and a decrease in blood pressure [58, 59]. Loss of
the usual nocturnal decrease in blood pressure is frequently seen in patients with
OSA [60, 61]. Finally, NREM sleep is associated with decrements in both global
cerebral blood flow and metabolism, both of which are particularly decreased during
slow wave sleep [62–64].
In contrast, during REM sleep, heart rate becomes increasingly variable with
transient increases in heart rate in association with the REMs. These transient
increases in heart rate are not observed following interruption of sympathetic neural
output to the heart in animals, suggesting that the surges in heart rate are sympa-
thetically driven [65]. In addition, heart rate variability is increased in REM sleep
compared to NREM sleep [57, 66]. In association with the transient increases in
heart rate, there are also transient increases in blood pressure. In addition, in animal
models, the transient increases in heart rate are associated with profound increases
in coronary blood flow [65]. In animal model of coronary stenosis, coronary blood
flow is decreased despite the increased heart rate [67], suggesting that the myocardium
is at increased risk of ischemia during REM sleep. However, human studies have
not been performed to confirm this finding. Finally, in contrast to NREM sleep,
global cerebral blood flow and metabolism are unchanged compared to wakefulness
in REM sleep [63]. However, there is evidence that there are significant regional
differences in cerebral blood flow during REM sleep, with increased blood flow to
areas of the brain associated with the generation of REM sleep such as the brainstem
and thalamus with continued decreased blood flow to other areas such as the prefrontal
and frontoparietal cortices [62, 68].
10 J.A. Rowley and M.S. Badr

Endocrine Function During Sleep

The levels of circulating endocrine hormones are generally influenced either by

circadian rhythms or the sleep–wake cycle [69, 70]. Growth hormone and prolactin
are examples of hormones whose circulating levels are related to the sleep–wake
cycle. Growth hormone secretion is tightly related to the sleep–wake cycle; when
the sleep period is shifted, the major growth hormone pulse is also shifted and the
growth hormone secretion is absent in sleep deprivation. Maximal growth hormone
secretion is during slow wave sleep, though this pattern is more generally observed
in men than women and is less pronounced with aging. While prolactin levels
generally increase in the afternoon after the usual nadir at noon, there is a major
elevation in prolactin levels shortly after sleep onset. In addition, during naps, there
is generally a pulse of prolactin activity irrespective of the time of day.
Adrenocorticotrophic hormone and cortisol follow a circadian pattern. Levels of
these hormones are generally increased in the later part of the night and are maximal
in the early morning; levels then decline through the day with minimal levels generally
around midnight.
Circulating levels of thyroid-stimulating hormone (TSH) are influenced by both
circadian rhythms and the sleep–wake cycle. TSH levels are low during the day and
increase in the evening under circadian influences. With sleep onset, levels decrease
with the inhibitory influence primarily noted during slow wave sleep. Consistent
with the sleep–wake cycle influence, TSH levels continue to increase during sleep
deprivation.

Gastrointestinal Function During Sleep

The effects of sleep on the gastrointestinal system are driven by a variety of processes,
including increased parasympathetic activity and circadian rhythms [71]. An example
of decreased parasympathetic activity is the observed decrease in salivation during
sleep. In contrast, basal gastric acid secretion follows a circadian rhythm, with peak
secretion between 10 pm and 2 am and relative absence of basal secretion in the
absence of meal simulation [72].
Sleep also affects the mobility of the gastrointestinal tract. The frequency of
swallowing decreases significantly during sleep while there is also evidence of
decreased esophageal peristaltic waves during NREM sleep [71, 73]. Traditionally,
it has been believed that upper esophageal sphincter tone is unchanged during sleep
while lower esophageal sphincter tone is decreased. However, recent data indicates
that upper sphincter tone is more vulnerable to decreased tone during sleep with a
smaller change in the lower esophageal sphincter tone, which generally stays greater
than intragastric pressure [73–75]. Finally, there is evidence that the phasic
myoelectrical activity and motor function of the stomach and intestines is decreased
1 Normal Sleep 11

during sleep, with some evidence that the decrease could be in part circadian in
origin [71, 73, 76, 77].
One of the major effects of the changes in gastrointestinal function during sleep
is increased acid contact time [78]. Generally, during wakefulness, gastroesophageal
reflux is a postprandial event and acid is rapidly cleared from the esophagus because
of increased salivary gland secretion, increased swallowing, and primary peristalsis.
While GER events are less frequent during sleep, events are associated with
decreased acid clearance and increased acid contact time because of the sleep-related
decreases in salivation, swallowing, and peristalsis. In addition, heartburn is a waking
conscious phenomenon and this sensation is generally absent during sleep. Increased
acid contact time has been shown to be related to proximal migration of refluxed
gastric contents [79] and is a potential mechanism for the development of esophagitis,
chronic cough, and exacerbations of bronchial asthma [71].

Summary of Keypoints

• Normal sleep is generally divided into four stages of sleep: N1, N2, N3 (all
stages of NREM sleep), and R (REM sleep). The stages of sleep are distinguished
by specific EEG and EOG characteristics.
• NREM sleep is characterized by the predominance of homeostatic mechanisms for
breathing, cardiovascular and gastrointestinal function, and thermoregulation.
• REM sleep is characterized by dreaming, inhibition of muscle activity, and insta-
bility of cardiopulmonary systems.
• In humans, sleep cycles between NREM and REM every 90–110 min with slow
wave sleep (N3) predominant in the first half of the night and REM sleep
predominant in the second half of the night.
• NREM sleep is associated with decreased tidal volume, stable respiratory rate,
decreased chemoresponsiveness to CO2 and O2, and increased PCO2 compared to
wakefulness. There is also autonomic stability with a vagal predominance, resulting
in bradycardia and frequent arrhythmia.
• While REM sleep is also associated with decreased chemoresponsiveness, there
is greater variability in respiration, heart rate, and regional blood, generally in
association with the REMs.
• Sleep is associated with changes in upper-airway structure and function
including decreased cross-sectional area, and increased resistance, compliance,
and collapsibility.
• Growth hormone and prolactin are tightly associated with the sleep cycle showing
increase during sleep. Adrenocorticotrophic hormone and cortisol demonstrate a
circadian rhythm with maximal levels in the early morning.
• Sleep is associated with decreased salivation, increased gastric acid secretion,
decreased swallowing and esophageal peristalsis, and overall decreased myo-
electrical activity of the gastrointestinal tract.
12 J.A. Rowley and M.S. Badr

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Chapter 2
Pharmacology of Sleep

Susmita Chowdhuri

Keywords GABA g(gamma)-amino butyric acid • Hypocretin antagonist

• Benzodiazepines • Nonbenzodiazepine receptor agonists • Melatonin receptor
agonist • Serotonin and norepinephrine reuptake inhibitors • Antidepressants
• Amphetamines • Modafinil • Sodium oxybate

Introduction

Drugs that modulate sleep and wakefulness operate by modifying the activity of key
sleep–wake neurotransmitters in the brain. Wakefulness-promoting nuclei include
the orexinergic lateral hypothalamus, the histaminergic tuberomammillary nucleus,
the cholinergic pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei, the
noradrenergic locus coeruleus, the serotonergic raphe nuclei, and the dopaminergic
ventral tegmental area (Table 2.1). The major sleep-promoting nucleus is the
GABAergic ventrolateral preoptic (VLPO) nucleus of the hypothalamus that sends
projections to the brainstem and hypothalamic wake promoting neurons in the locus
coeruleus, raphe nucleus, and tuberomammillary nucleus and these in turn send
projections to the VLPO. Reciprocal inhibition of these neurons promotes sleep
and wakefulness [1]. In addition, the hypocretin/orexin neurons in the lateral
thalamus reinforce and stabilize the wake promoting area [1]. Glutamate is also
wake promoting.
Sedatives and stimulants modulate the activity of these sleep and wake promoting
nuclei. Overall, drugs that are agonistic to the sleep-promoting GABA receptor or
that are antagonistic to the wake-promoting neurotransmitters, norepinephrine, sero-
tonin, histamine, and acetylcholine, are sedating [2]. Conversely, drugs that activate

S. Chowdhuri (*)
Sleep Medicine Section, Medical Service, John D. Dingell VA Medical Center
and Wayne State University, Detroit, MI, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 17
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_2,
© Springer Science+Business Media, LLC 2012
18 S. Chowdhuri

Table 2.1 Neurotransmitters and sleep

Sleep promoting neurotransmitters/neurohormone Wake promoting neurotransmitters
GABA Norepinephrine
Adenosine Dopamine
Melatonina Serotonin
Acetylcholine
Histamine
Hypocretin/orexin
Glutamate
GABA g-amino butyric acid
a
Melatonin is a neurohormone

the same wake-promoting neurotransmitters are wake promoting. [2] Over the last
few years, several new prescription drugs have been introduced into the market that
target one or more of these neurotransmitters and many more are in the pipeline.
This chapter discusses the drugs that are used or prescribed for their sedating or
stimulant effects. Dopamine agonists are used for the treatment of periodic limb
movements and are discussed elsewhere in the book.

Sleep-Promoting Drugs

The potentiation of GABA or inhibition of wake promoting neurotransmitters produces

sedation. Accordingly, sedative action depends on binding of the drug to the
corresponding receptor (Fig. 2.1). GABA is the major sleep promoting neurotrans-
mitter (g(gamma)-amino butyric acid). Drugs that potentiate sleep via GABA act by
binding to the GABAA receptor [3]. The GABAA receptor is a pentameric protein com-
plex regulating a transmembranous chloride channel. It is comprised of five subunits,
typically a combination of two alpha, two beta, and one gamma, 2a(alpha)
2b(beta)1g(gamma). Binding of a drug to one or more subunits leads to allosteric
changes in the GABAA complex with resultant opening of the chloride channel.
Negatively charged chloride ions enter into the cell via the open chloride channel inhib-
iting neuronal activity. The a (alpha)1 subunit specifically mediates sedation [3].
Additionally, the melatonin receptor agonists that are used as sedatives are
discussed. The remaining drugs reviewed in this section are drugs that produce
sedation, as a secondary effect via antihistamine, antiserotonin, or antiadrenergic
activity, and are used off-label, except for doxepin, Fig. 2.1. The newest agent in
development is an orexin/hypocretin antagonist.

Benzodiazepines

Benzodiazepines had been the mainstay of pharmacotherapy for insomnia for the
past several decades. Benzodiazepines bind nonselectively to the GABAA receptor,
2 Pharmacology of Sleep 19

Mechanism Drugs / Drug

of action categories

Non-BDZ receptor
GABA agonist agonists
Benzodiazepines
Barbiturates*,alcohol ¶

Melatonin Ramelteon
receptor agonist Tasimelteon
Antihistamine drugs*
Trazodone*
Histamine
Sleep antagonists Doxepin, low dose
Promoting Mirtazapine *
Drugs
Serotonin Trazodone*
receptor Doxepin
antagonism Mirtazapine*

Trazodone*
Norepinephrine /
dopamine / Olanzepine*
acetylcholine Quetiapine*
antagonism Tricyclic antidepressants*
Mirtazapine*

*Off label use; BDZ Benzodiazepine, only flurazepam, quazepam, estazolam and temazepam are
FDA approved for insomnia; MAOI: Monoamine oxidase inhibitors; ¶ Alcohol is commonly
self-administered for use as a sedative

Fig. 2.1 Overview of drugs that are sleep promoting and their site(s) of action

and hence, in addition to sedation, also mediate antianxiety, anticonvulsant,

anterograde amnesia, and myorelaxant effects. Benzodiazepines increase sleep
duration [4–6] and modify the sleep architecture by slow-wave sleep (SWS) and
rapid-eye movement (REM) sleep. They also promote increased sleep spindles.
Based on the duration of action, they can be categorized into short-, intermediate-,
and long-acting agents (Table 2.2). Benzodiazepines have been associated with a
number of dose-dependent adverse effects, including daytime drowsiness due to
hangover effect, dizziness, anterograde amnesia, tolerance, drug dependence, and
upon withdrawal, rebound insomnia, REM rebound. Withdrawal symptoms, including
seizures, following drug cessation [4–6] limit their use. The drugs should be tapered
slowly to avoid withdrawal effects. The longer acting drugs produce next day “hang-
over” effects due to residual sedation, while the shorter acting drugs are more prone
to cause drug dependence, anterograde memory loss, and rebound insomnia.
20 S. Chowdhuri

Table 2.2 Pharmacokinetics and dosing of benzodiazepines

Generic name Trade name Dose mg Half-life (h) Peak effect (h)
Long acting (>24 h)
Flurazepama Dalmane 0.125–0.6 48–250 0.5–1
Quazepama Doral 7.5–1.5 41–250 2
Diazepam Valium 5–10 20–50 1–1.5
Intermediate acting (6–24 h)
Estazolama ProSom 1–2 10–24 2
Temazepama Restoril 7.5–30 3.5–18 1.2–1.6
Lorazepam Ativan 0.5–2 g 10–20 2–4
Oxazepam Serax 10–15 5–20 3
Short acting (<6 h)
Triazolama Halcion 0.125–0.5 1.5–5.5 1–2
a
FDA approved agents for chronic insomnia

Benzodiazepines are pregnancy category D or X drugs. Only flurazepam, quazepam,

estazolam, and temazepam are FDA approved as hypnotics for the treatment of
insomnia; however, other benzodiazepines are routinely used off-label despite lack
of adequate data regarding their efficacy and safety (Table 2.2) [7–9].

Nonbenzodiazepine Receptor Agonists (NBRA)

The search for an ideal agent that specifically targets insomnia led to the development
of the nonbenzodiazepine receptor agonists (NBRAs). Unlike the benzodiazepines,
the NBRAs have no anxiolytic, myorelaxant, and anticonvulsant properties but have
very strong hypnotic properties due to their selective binding to the a(alpha)1 subunit
of the GABAA receptor. An ideal therapeutic agent for insomnia should aim to treat
both sleep onset and sleep maintenance insomnia without significant residual
hangover effects, tolerance, or rebound insomnia upon stopping. The NBRAs were
developed keeping these characteristics in mind. The three NBRA agents available
in the USA, zolpidem, zaleplon, and eszopiclone are FDA approved for short-term
use for insomnia. In addition, zolpidem modified release (Ambien® CR) and eszopi-
clone are approved for long-term use for up to 6 months for insomnia for sleep
maintenance insomnia [10]. The pharmacologic properties of these drugs are
presented in Table 2.3. Zopiclone is not available in the US market and is not discussed
here. Zolpidem is currently available for use both via oral and sublingual routes.
A recent crossover multicenter study revealed that sublingual zolpidem significantly
shortened latency to persistent sleep (LPS) by 34% (10.3 min) as compared to oral
zolpidem (p = 0.00) [11].
Side effects: Potential side effects of NBRAs are enumerated in Table 2.3. Most
frequent adverse events for zolpidem extended-release were headache, anxiety, and
somnolence. No rebound effect was observed during the first three nights of discon-
tinuation [12]. In contrast, in a 4-week study of zaleplon and zolpidem in adults
 2

Table 2.3 Pharmacology of NBRAs

Generic name Zolpidem Zaleplon Eszopiclone
Trade name Ambien Sonata Lunesta
Chemical structure Imidazopyridine Pyrazolopyrimidine Cyclopyrrolone (s-isomer)
Elimination half-life Zolpidem tartrate: 2.6 h (2.9 h elderly) 1h 6h
Zolpidem MR: 2.8 h, provides extended
plasma concentrations beyond 3 h after
Pharmacology of Sleep

administration
Drug metabolism Cytochrome P450 Aldehyde oxidation Cytochrome P450
Recommended dose 10 mg 10 mg 2–3 mg
Dose adjustment Elderly or hepatic impairment:5 mg, Elderly: 5 mg Elderly: 1–2 mg
(modified release: 6.25 mg) Hepatic impairment: 1 mg
Indication (s) Short acting: sleep onset modified release: Sleep onset only Sleep onset and sleep maintenance
sleep onset and maintenance
Pregnancy warning Pregnancy category C Pregnancy category C Pregnancy category C
Controlled substance Schedule IV Schedule IV Schedule IV
Drug-drug interaction CNS suppressants [191] CNS suppressants [192] CNS suppressants [178]
Increased drug levels with inhibitors Increased drug levels with Increased levels with inhibitors of
of CYP3A4 e.g., azole antifungals; inhibitors of both aldehyde CYP3A4 e.g., itraconazole, ketocon-
decreased drug levels with inducers oxidase and CYP3A4 e.g., azole, clarithromycin, ritonavir,
of CYP3A4 e.g., rifampicin cimetidine, erythromycin nelfinavir; decreased drug levels with
inducers of CYP3A4 e.g., rifampicin
Adverse effects Residual sedation, rebound insomnia, Headache, abdominal Same as zolpidem
complex behaviors pain, nausea, dizziness,
Reports of anaphylactoid reaction [191] somnolence [192] In addition, unpleasant taste,
dry mouth, somnolence, headache,
and dizziness [30]
NBRA nonbenzodiazepine receptor agonists; MR modified release; h hour; CNS central nervous system
21
22 S. Chowdhuri

with chronic insomnia, significant rebound and withdrawal effects were observed
in the zolpidem group [13]. There is little potential for drug dependence with
these agents. The incidence of dependence is lower than that of benzodiazepines.
In extreme cases, dose increases reached a factor of 30–120 above the recom-
mended doses. The majority of patients demonstrating drug dependence had a
history of former drug or alcohol abuse and/or other psychiatric conditions [12].
Patients should be counseled to take these medications as they get into bed and only
when they are able to stay in bed a full night (7–8 h) before being active again. In a
crossover double-blind administration of zaleplon 10 mg, zolpidem 10 mg, or placebo,
healthy subjects were awakened and given medication at times 5, 4, 3, or 2 h before
morning awakening, which occurred 8 h after bedtime [14]. Zaleplon was free of
residual sedative effects when taken as little as 2 h before waking in normal subjects.
In contrast, residual effects of zolpidem were still apparent on objective assessments
up to 5 h after nocturnal administration. Complex behaviors such as “sleep-driving”
(i.e., driving while not fully awake after ingestion of a sedative hypnotic, with amnesia
for the event) have been reported with sedative hypnotics, including zolpidem [15].
Although behaviors such as “sleep-driving” may occur with zolpidem tartrate at
therapeutic doses, the concomitant use of alcohol and other CNS depressants
increases the risk. The drug should be discontinued in patients who report a “sleep-
driving” episode. Rare occurrence of angioedema involving zolpidem is listed on the
package insert [191]. Zolpidem modified release tablets should not be crushed, divided,
or chewed, and should not be taken with or immediately after a meal.
Efficacy studies: There are few head-to-head trials comparing the three NBRAs.
Clinical placebo-controlled trials investigating efficacy of zolpidem, zaleplon, or
eszopiclone have reported on sleep quality and drug effects on sleep architecture.
These are presented in below and in Table 2.4 [10–15, 17–35]. Employed adults
with chronic insomnia treated with zolpidem extended-release 12.5 mg experienced
significantly improved work performance over 24 weeks [26]. There were sustained
improvements on sleep with decreased sleep latency, wake time after sleep onset,
number of awakenings, increased total sleep time and sleep quality. Ratings of
daytime ability to function, alertness and sense of physical well-being, compared
to baseline, were also noted after 6 months of eszopiclone [32]. Furthermore,
12 months of nightly treatment with eszopiclone 3 mg was also well tolerated
and tolerance was not observed [28]. Additionally, eszopiclone improved CPAP
compliance: a short course (24 month) of 3 mg eszopiclone during the first 2 weeks
of CPAP improved adherence with 20.8% more nights and for 1.1 h more per
night of CPAP use [31]. Long-term nightly use of eszopiclone (3 mg) for primary
insomnia enhanced quality of life, reduced work limitations, and reduced global
insomnia severity [36]. Eszopiclone was also cost-effective for the treatment of
primary insomnia in adults, especially when lost productivity costs were included
[37]. Over a 6-month period, eszopiclone use resulted in a net gain of 0.0137 QALYs
over placebo at an additional cost of $67, resulting in an incremental cost per QALY
gained of slightly less than $5,000.
Comparison with benzodiazepines: One meta-analysis, comprising of 24 eligible
studies with a total study population of 3,909, concluded that due to poor methodological
 2

Table 2.4 Studies investigating NBRA efficacy

Study design, comparison,
author, year Subject Dose of active drug PSG vs. questionnaires Results: sleep parameters and other measures
RCT/placebo multicenter, N = 615, age 42 ± 12.9 y, Zaleplon, 5, 10, or 20 mg; PSG not done Sleep questionnaires; Median SL significantly
parallel group, 18–65 y zolpidem, 10 mg; or placebo, lower with zaleplon, 10 and 20 mg, than
Elie et al. [13] 4 weeks with placebo during all 4 weeks of
treatment and with zaleplon, 5 mg, for the
first 3 weeks. Zolpidem, 10 mg, signifi-
Pharmacology of Sleep

cantly decreased SL, increased sleep

duration, and improved sleep quality.
Zaleplon, 20 mg, also significantly
increased sleep duration compared with
placebo in all but week 3 of the study.
Post sleep questionnaires Rebound insomnia with the zolpidem. No
rebound with zaleplon.
RCT/placebo Fry et al. [18] N = 355, age 40 ± 13 Zaleplon 5, 10, and 20 mg PSG not done Zaleplon 20 mg decreased SL, significant
43 y, 18–65 compared to placebo; effects on sleep duration, number of
zolpidem 10 mg as active awakenings. Zaleplon 10 mg had no effect
comparator;4 weeks on number of awakenings. Zolpidem 10 mg
significantly improved sleep latency, sleep
duration, and sleep quality.
Postsleep questionnaires Greater withdrawal symptoms with zolpidem
Randomized, multicenter, N = 53, mean age 52.2 y, 40 10 mg zolpidem vs. 10 mg PSG not done Questionnaire: 62% of patients preferred
crossover, Allain et al. and 65 y, primary zaleplon, 2 consecutive nights Sleep Questionnaire, visual zolpidem, while 38% preferred zaleplon
[19] insomnia with 1 night on each drug analogue scale (VAS) (p = 0.08). The quality of sleep items
getting to sleep and quality of sleep were
significantly improved after zolpidem
(p = 0.03 and p < 0.0001, respectively).
VAS: subjective sleep quality was
significantly better after zolpidem
(p < 0.0001).
(continued)
23
Table 2.4 (continued)
24

Study design, comparison,

author, year Subject Dose of active drug PSG vs. questionnaires Results: sleep parameters and other measures
RCT/placebo multicenter, N = 199, age 41.0 ± 12.8 y, 10 mg zolpidem, 3–5 pills/week, PSG not done 42% decrease in sleep latency; no tolerance, no
parallel, Perlis et al. [20] 25–60, primary insomnia 12 weeks Sleep diary dose escalation, and no evidence of
rebound insomnia. Fifty two percent
reduction in number of awakenings, a 55%
decrease in wake time after sleep onset, and
a 27% increase in total sleep time.
RCT/placebo multicenter, N = 1018, age 18–64 y, 12.5 mg zolpidem MR, 24 PSG not done Zolpidem MR was significantly superior to
parallel, Krystal et al. [21] primary insomnia weeks, 3–7 day run – in and Sleep questionnaire placebo with improved TST, WASO and SL
7 day run-out phase (p £ 0.0014). Patient’s global impression
scores significantly favorable for zolpidem
MR.
RCT/placebo multicenter, N = 593, age 21–69 y, 3 mg eszopiclone, 6 months PSG not done At 6 month- drug vs. placebo, SL: 47.0 vs.
parallel, Krystal et al. [22] primary insomnia Interactive voice-response 63 mina; WASO 44 vs. 48 mina; at 6
system (IVRS) month-TST: 378 vs. 339 mina; awakenings/
night: 1.9 vs. 2.6a; sleep quality and
alertness were improveda.
RCT/placebo multicenter, N = 308, age 21–64, primary 2–3 mg eszopiclone, 44 nights PSG and patient reports 2 mg dose did not significantly improve sleep
parallel, Zammit et al. insomnia maintenance
[27] 3 mg had significantly less time to sleep onset
(p < or = 0.0001), more total sleep time and
sleep efficiency (p < or = 0.0001), better
sleep maintenance (p < or = 0.01), and
enhanced quality and depth of sleep
(p < 0.05) across the double-blind period
compared with placebo. Average SL was
33.0 min for placebo and 23.0 minutes and
18.0 min, for the 2 and 3 mg doses respectively
(p < 0.01).There was no evidence of
tolerance or rebound insomnia after therapy
discontinuation. Digit-symbol substitution
test showed no decrement in psychomotor
S. Chowdhuri

performance next day.

Study design, comparison,
author, year Subject Dose of active drug PSG vs. questionnaires Results: sleep parameters and other measures
2

RCT/placebo multicenter, N = 231, age 65–85 y, 1–2 mg eszopiclone, 2 week PSG not done Patient-reported data via IVRS at week 2, drug
parallel, Scharf et al. [29] primary insomnia IVRS vs. placebo: 1 mg: SL, min: 43.3 vs. 65a;
2 mg: 48 vs. 65a; WASO, min: 1 mg: 63 vs.
67a; the 2 mg dose had similar effects on
WASO and awakenings at night TST, min:
1 mg dose: 357 vs. 349a; 2 mg dose: 379.1
vs. 349a.
RCT/placebo multicenter, N = 264, age 64–86 y, 2 mg eszopiclone, 2 weeks PSG measurements and Patient report: LPS, min: 15 vs. −30a; WASO,
parallel, McCall et al. [30] primary insomnia patient report min: 82 vs. 91a; number of awakenings
unchanged; PSG: TST, min:385 vs. 358a;
Pharmacology of Sleep

SE,%: 80 vs. 75a; increased stage 2

sleep,%: 2.3 vs. −0.1; no change in
REM,SWS compared with placebo; SL
min: 30 vs. 41a; WASO, min: 75 vs. 91a;
TST, min: 387 vs. 324a; ISI score: −6 vs.
−4a; fewer naps with drug vs. placebo.
RCT/placebo multicenter, N = 65, age 21–64 y, primary Eszopiclone 1, 2, 2.5, or 3 mg PSG measurements All active treatments significantly reduced
crossover study, Erman insomnia vs. zolpidem 10 mg vs. median LPS relative to placebo by 42–55%
et al. [31] placebo; two nights each (LPS 13–16 min with drug); higher SE with
eszopiclone 2, 2.5, and 3 mg, and zolpidem
10 mg compared with eszopiclone 1 mg;
WASO was significantly lower for
eszopiclone 3 mg but not for zolpidem
10 mg or the other eszopiclone doses.
RCT/placebo Ancoli Israel N = 388, age 65–85 y, 2 mg eszopiclone, 12 weeks PSG not performed Electronic sleep/wake diaries TST: 12 wks vs.
et al.[34], Phase IV trial primary insomnia, study, 2-week run out, Electronic sleep/wake baseline: 360.08 vs. 297 min; SL: 24.62 vs.
comorbid depression, 4-week follow-up diaries 19.92 min; WASO decrease of 36 min
dementia
(continued)
25
Table 2.4 (continued)
26

Study design, comparison,

author, year Subject Dose of active drug PSG vs. questionnaires Results: sleep parameters and other measures
RCT, crossover study, N = 59, age 40–65 y, peri/ 3 mg eszopiclone, 11 weeks PSG not performed Sleep diary: difference between eszopiclone
placebo, Joffe et al. [35] postmenopausal women, and placebo.
menopause-associated Sleep diary TST 66.5 mina; SL 17.8 mina; SE: 15%a,
insomnia WASO: 37.7 mina. Reduced ISI scores by
8.7 pointsa. Eszopiclone improved all sleep
parameters, depressive symptoms, anxiety
symptoms, quality of life, and nighttime
but not daytime hot flashes.
PSG polysomnography; RCT randomized controlled trial; N number; y year; wks weeks; LPS latency to persistent sleep; TST total sleep time; SE sleep effi-
ciency; AHI apnea hypopnea index; REM rapid-eye movement sleep; SWS slow wave sleep; ISI insomnia severity index score; WASO wake time after sleep
onset; SL sleep latency; IVRS interactive voice response system; VAS visual analogue scale; MR modified release, % percentage
a
p<0.05, drug vs. placebo
S. Chowdhuri
2 Pharmacology of Sleep 27

quality, secondary to insufficient or inappropriately reported data, a clear distinction

between benzodiazepines and NBRA could not be made apart from those arising
from pharmacokinetic properties [38]. For a review of comparisons of NBRAs
with benzodiazepines, the reader is referred to detailed meta-analysis and reviews
completed elsewhere [7, 8, 38, 39].

Barbiturates Derivatives

Barbiturates and their derivatives (i.e., glutethimide, chloral hydrate) also potentiate
GABA and have been used as sedatives. They are no longer in use as sedatives due
to risk of significant adverse effects, development of tolerance, and dependence
with long-term use [40].

Melatonin Receptor Agonists

Ramelteon

Ramelteon is a synthetic analog of melatonin and a melatonin receptor agonist.

Ramelteon acts by binding selectivity to the MT1 and MT2 receptors, two G-protein
coupled receptors [41]. The melatonin MT1-receptor and MT2-receptor mRNA in
the suprachiasmatic nucleus (SCN) mediate SCN firing by melatonin [42] and the
phase-shifting effects of melatonin on circadian rhythms [43, 44], respectively.
Ramelteon’s positive effects on sleep are associated with an attenuation of the
circadian rise in core body temperature and an increase in skin temperature [45].
The magnitude of the increase in skin temperature is correlated with a faster latency
to sleep with ramelteon.
Pharmacologic characteristics: Peak concentration of the drug is reached in 0.75 h
when fasting [46]. It should be taken on an empty stomach as peak concentrations are
reduced by 25% after a meal. It undergoes a high first-pass metabolism in the liver
[47, 48]. Elimination half-life of ramelteon at an 8-mg dosage is 2–5 h [46]. Clearance
is reduced in the elderly due to a longer half-life in the elderly age group 60–79 year
(1.9 h) vs. younger age group (1.3 h) [48]. Studies suggest a flat dose–response across
dosages of 4–32 mg [49]. The recommended dose is 8 mg at bedtime [46].
Ramelteon has not been shown to produce dependence and has no potential for
abuse unlike the GABAergic drugs [50]. In a study of substance abusers given
ramelteon or triazolam, ramelteon did not demonstrate any potential for abuse lia-
bility [50] or withdrawal. It is currently the only nonscheduled prescription drug
that is FDA approved for the treatment of sleep-onset insomnia.
Drug–drug interactions: There is significant drug interaction with fluvoxamine co-
administration, resulting in a more than 100-fold increase in the levels of ramelteon
[51] and the two drugs should not be combined. Ketoconazole (CYP3A4 inhibitor)
increases ramelteon levels whereas rifampin (CYP enzyme inducer) decreases
28 S. Chowdhuri

effects of ramelteon [46]. Doxepin and fluconazole also increase systemic exposure
of ramelteon [46].
Drug efficacy and tolerance: Overall, melatonin reduced sleep onset latency with
no consistent or clinically appreciable effects on measures of sleep maintenance.
Several trials have evaluated the efficacy of ramelteon on sleep onset and mainte-
nance [16, 49–63], see Table 2.5. Psychomotor performance was not reduced the
next day or during the night with ramelteon [49, 52], and there were no significant
next-morning residual effects [52, 58, 59] observed via Digit Symbol Substitution
Test (DSST), memory recall tests (immediate and delayed), visual analog scales
(feelings and mood), and Postsleep Questionnaire (level of alertness and ability to
concentrate) [52]. In a 6-month efficacy study, there was no decrease in the
morning level of alertness or the ability to concentrate throughout the study dura-
tion. There was no rebound insomnia after discontinuation of the drug [54].
Similarly, there was no evidence of significant rebound insomnia or withdrawal
effects following treatment discontinuation after 5 week in older adults [53].
Ramelteon did not impair middle-of-the-night balance, mobility, or memory rela-
tive to placebo [16]. Ramelteon also did not produce oxygen desaturation or
increase apnea–hypopnea index in subjects with mild to severe COPD [60, 61].
It is a pregnancy category C drug.
Incidentally, ramelteon’s new drug application was recently denied in Europe
based on lack of evidence for effectiveness. The evaluation committee was
“concerned that the company had not demonstrated a long-term effectiveness of
ramelteon and that the benefit of ramelteon had not been sufficiently demonstrated
and any benefits did not outweigh the identified risks.”
Data regarding ramelteon’s circadian phase shifting efficacy are limited.
Ramelteon reentrained the light–dark cycle in an animal study [177] and also in
recent studies in healthy humans with phase advance [187, 188]. Chronobiotic effect
of ramelteon was affected by level of light exposure. Further evaluations in indi-
viduals with circadian rhythm sleep disorders are warranted.
Side effects: The incidence of adverse effects was low. The most commonly reported
treatment-emergent adverse effects were dizziness (ramelteon, 8.9%; placebo,
7.1%), dysgeusia (ramelteon, 7.0%; placebo, 2.9%), myalgia (ramelteon, 6.4%; pla-
cebo, 3.5%), and headache (ramelteon, 5.1%; placebo, 5.9%) [59, 60]. Angioedema
and anaphylaxis have been reported [46, 60, 61]. Long-term exposure to ramelteon
16 mg, a potent melatonin receptor agonist, resulted in mild, transient increase in
prolactin, in women only, with no measurable reproductive effects [51].

Tasimelteon

Tasimelteon, another melatonin MT1/MT2 agonist studied in a phase III trial

demonstrated that in a model of abrupt advance in sleep time, the drug produced
improved sleep latency, sleep efficiency, and wake after sleep onset [190]. The fre-
quency of adverse events was similar between tasimelteon and placebo.
 2

Table 2.5 Studies investigating ramelteon efficacy

Study design, compari- Dose of active
son, author, year Subject drug PSG vs. questionnaires Results: sleep parameters and other measures
RCT/placebo N = 375, age 35–60 y, 16 and 64 mg PSG, postsleep question- PSG LPS, min, – 8 mg: 14 vs. 24a; 16 mg: 22 vs. 31a
multicenter, Roth healthy adults, naire, digit symbol TST, min, – 8 mg: 25 vs. 411a;16 mg: 422 vs. 411a
Pharmacology of Sleep

et al. [56] transient insomnia, substitution test There were no significant differences among the groups for
one night (DSST) DSST scores, suggestive no residual sleepiness.
RCT/placebo N = 107, age 18–64 y, 4, 8, 16, and PSG, postsleep question- All tested doses of Ramelteon resulted in statistically
multicenter, primary insomnia, 32 mg naire, VAS, DSST significant reductions in PSG LPS (by approximately
crossover, Erman two nights at each 7–8 min) and increases in TST (by approximately
et al. [49] dose 2–8 min). No differences in WASO compared with
placebo. No next-day residual effects noted at any dose
There were no differences in adverse events (headache,
somnolence, sore throat).
RCT/placebo N = 405, age 18–64 y, 8 and 16 mg, 5 PSG, postsleep question- PSG LPS, min, – 8 mg: 32 vs. 47.9a at week 1; maintained
multicenter, primary insomnia weeks naire, VAS, DSST at weeks 3 and 5
Zammit et al. [58] PSG TST, min, – 8 mg-394 vs. 375a at week 1; maintained
at weeks 3 and 5
Similar effects were noted with the 16-mg dose. Wake time
after sleep onset and number of awakenings were not
significantly different with ramelteon 8 or 16 mg. No
effect on sleep architecture, next-day psychomotor
tasks, alertness, or ability to concentrate. No withdrawal
or rebound effects were observed.
(continued)
29
Table 2.5 (continued)
30

Study design, compari- Dose of active

son, author, year Subject drug PSG vs. questionnaires Results: sleep parameters and other measures
RCT, placebo, N = 829, age > or = 64 4 and 8 mg, 5 PSG, sleep diary PSG SL, min, – 4 mg: 70 vs. 78a at week 1; maintained at
multicenter, Roth (64–93 y), primary weeks week 5
et al. [53] insomnia PSG SL, min, – 8 mg: 70 vs. 78a at week 1; maintained at
weeks 3 and 5
PSG TST, min – 4 mg: 324 vs. 313a at week 1; 336 vs. 324a
at week 3
PSG TST, min – 8 mg: 321 vs. 314a at week 1; 8 mg: 332
vs. 324 at week 3; no differences at week 5. No rebound
insomnia or withdrawal effects were noted.
RCT, crossover study N = 100, age 65–83 y, 4 and 8 mg, 9 PSG, postsleep question- PSG LPS, min, – 4 mg: 28.7 vs. 38.4a
placebo, multi- primary insomnia, weeks naire, VAS, DSST PSG LPS, min, – 8 mg: 30.8 min vs. 38.4a
center, Roth et al. two nights each at Total sleep time (p = 0.036 and p = 0.007, respectively) and
[52] each dose sleep efficiency (p = 0.037 and p = 0.007, respectively)
were also significantly improved with ramelteon 4 and
8 mg, respectively. No residual daytime effect noted.
RCT/placebo N = 157, mean age 72.7 8 mg, 5 weeks Sleep diary Reductions in subjective SL, min from baseline: −23 vs.
multicenter, y, severe sleep-onset −7.5 at week 1; sustained at week 3 and 5
posthoc analysis, difficulty in primary
Mini et al. [63] insomnia (subjective
sleep latency
>60 min)
RCT, multicenter, N = 451, age 18–79 8 mg, 6 month PSG and morning Reductions in LPS, min – week 1: 381 vs. 365a; significant
placebo, Mayer (mean 46) y, questionnaires, DSST, decreases were observed at week 1 and months 1, 3, 5,
et al. [54] primary insomnia VAS and 6 (p < 0.05). No significant change in TST,
subjective number of awakenings and sleep quality. No
next-day residual effects. No withdrawal symptoms or
rebound insomnia were detected after discontinuation.
For annotations, see Table 2.3 and 2.4
a
S. Chowdhuri

p<0.05, drug vs. placebo

2 Pharmacology of Sleep 31

Melatonin

Melatonin is a neurohormone of the pineal gland that is modulated by the SCN of

the hypothalamus. Regulation of melatonin synthesis by the SCN determines the
circadian rhythm of sleep and wakefulness [1]. Synthetic melatonin is available
over the counter as a “nutritional supplement.” Melatonin has hypnotic effects and
in doses of 0.1–12 mg has been used as a sedating agent, for the treatment of
sleep-onset insomnia and insomnia related to jet lag, shift-work sleep disorder
(SWSD), and delayed sleep phase disorder, but with variable efficacy. The reader is
referred to excellent systematic reviews [64–68]. Melatonin was effective in
entraining free-running blind individuals [69]. Melatonin may also be effective in
the management of REM sleep behavior disorder [70]. The drug has few side effects
including headache, dizziness, nausea, or abdominal cramps [71]. Purity of the drug
must be ascertained prior to its use.

Antidepressants and Antipsychotics

A number of antidepressants cause sedation as a secondary effect and practitioners

have used these drugs off-label to treat insomnia. This is despite the fact that
there are very few controlled, short- or long-term studies to validate their safety and
efficacy for use in patients with primary insomnia and these drugs, other than the
recently approved low-dose doxepin, cannot be recommended as first-line pharma-
cotherapy in primary insomnia. Other antidepressants may produce insomnia as
described below.

Trazodone

Trazodone probably produces sedation by blocking the 5HT-2a/2c receptor. Prior to

the introduction of NBRAs in the 1990s, trazodone was the most highly prescribed
drug for insomnia. This is despite the fact that the efficacy of trazodone for
treatment of insomnia had been studied in only small populations for insomnia in
depressed individuals, usually with limited subjective sleep evaluations of sleep
duration, sleep latency, or nocturnal awakenings and without objective polysomno-
graphic data. In one such study (N = 17), trazodone was reportedly effective for
patients with insomnia related to antidepressant (fluoxetine or bupropion) use,
with increased Pittsburgh index of sleep duration but unchanged Pittsburgh
index measures of sleep efficiency [72]. In six depressed patients with significant
sleep disturbances in an 8-week single-blind study design, trazodone (150–400 mg)
produced a 44% improvement in persistent sleep latency, total sleep time, and sleep
efficiency with a doubling of stage IV sleep [73]. There was no change in percentage
of REM; however, REM latency increased 28%. Trazodone 100 mg given over
32 S. Chowdhuri

7 days increased TST and SWS and decreased awakenings in patients with sleep
disruption due to antidepressants compared with placebo [74] (Tables 2.6 and 2.7).
In addition, data in nondepressed patients is limited. In a 2-week, parallel group
study in nondepressed primary insomniacs, comparing trazodone 50 mg and zolpidem
10 mg, only zolpidem maintained a significantly shorter sleep latency than the placebo
group, with no differences in sleep duration among the groups at week 2 [75].
Side effects: Potential adverse reactions include dizziness, dry mouth, nausea/
vomiting, constipation, headache, orthostatic hypotension, ventricular arrhythmias/
torsades de pointes [76, 77], and, rarely, priapism [78]. This should caution physi-
cians against routine use of trazodone for insomnia, especially in the elderly [79, 80].

Tricyclic Antidepressants (TCA)

Tricyclic Antidepressant (TCA) agents produce sedation via their antihistaminergic

and anticholinergic properties [81–85]. These are presented in Tables 2.6 and 2.7.
The TCA are limited by their anticholinergic side effects. Clomipramine, amitrip-
tyline, and doxepin are more sedating than other TCAs, while desipramine is the
least sedating. These drugs are linked with increased periodic leg movements.
However, based on efficacy and safety studies, the FDA recently approved low-dose
doxepin (Silenor® 3, 6 mg) as the first antidepressant with an indication for the treat-
ment of sleep maintenance insomnia [86–89]. The drug has high specificity and
affinity to the histamine H(1) receptor and this property of doxepin makes it a good
sedative at low doses without the concomitant major anticholinergic side effects.

SSRI and SNRI

SSRIs may be associated with daytime insomnia or sedation, depending on their

effect on different serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes. They
suppress REM sleep and delay REM latency. The serotonin and norepinephrine
reuptake inhibitor (SNRI), e.g., venlafaxine and duloxetine also produce sleep frag-
mentation, insomnia, and suppress REM sleep [81] (Tables 2.6 and 2.7). Stimulation
of the 5-HT2 receptors may contribute to insomnia and the observed changes in
sleep architecture with SSRIs or SNRI. However, daytime sedation has also been
observed with fluoxetine [90]. The SSRIs may have paradoxical daytime sedating
effect, with fluvoxamine being the most sedating. SSRIs have been associated with
increased eye movements in NREM sleep [91, 92] and periodic leg movements on
polysomnography. They have also been associated with increased REM sleep
without atonia [93]. Two excellent reviews have addressed the variable effects of
antidepressants on sleep [81, 94]. Side effects of SSRIs included gastrointestinal
adverse effects (nausea and diarrhea), headache, dizziness, hypotension, agitation,
insomnia and tremor, weight gain, and sexual dysfunction. Compared to TCAs,
SSRIs have fewer anticholinergic effects. Of the SSRIs, paroxetine is pregnancy
class D and the rest are pregnancy class D.
2 Pharmacology of Sleep 33

Table 2.6 Overview of the site of action and effect on sleep architecture of sedatives and psycho-
active drugs
Effect on sleep duration, sleep latency and
Drug Mechanism of action sleep architecture
Benzodiazepines GABAA receptor-nonspecific Increased TST, short SOL, decreased SWS,
binding and decreased%REM, increased stage 2,
pseudospindles
NBRAs GABAA- a (alpha)1 subunit Increased TST, increased sleep efficiency,
short SOL, unchanged sleep architecture
Barbiturates Opens chloride channel Increased TST, short SOL, decreased SWS,
and decreased%REM
Valerian Agonist:GABA receptor, A(1) Decreased SOL, increased SWS (after
adenosine or 5-HT-2a prolonged use), no change in REM sleep
Gabapentin Mechanism for somnolence is Increased SE, increased SWS%, decrease in
not clear in humans arousals, and stage 1 sleep
Ramelteon MT1/MT2 receptor agonist Increased TST, short SOL, no changes in
SWS, REM sleep percentages or WASO
Almorexanta Orexin receptor antagonist Results pending, preliminary results show
reduced WASO
Mirtazapineb 5-HT2/5-HT3 antagonist, Increased TST and SE, decreased SOL, no
central alpha2-adrenergic significant change in REM [179]. In
antagonist, H1 antagonist another study [180], mirtazapine increased
total SWS and the SWS in the first sleep
cycle, but not SWS in the second sleep
cycle, increased REM latency, the duration
of the first REM episode and decreased the
number of REM episodes. Reduced
WASO
Trazodoneb specific inhibitor of synapto- Decreased stage 2, increased SWS, slight
somal reuptake of decrease/increase in REM sleep
serotonin, 5HT2 and 5HT3
antagonist, H1 antagonist,
alpha 1 blockade
Doxepin, low Selective H1 receptor Increased TST and SE, decreased SOL and
dose (6 mg) antagonist, WASO/awakening, increased stage 2,
alpha1antagonist increased stage N2 and N3,
decreased%REM sleep
Bupropionb Dopamine and norepinephrine Increased REM sleep%, decreased periodic
reuptake inhibition limb movements, insomnia
TCA H1 antagonist, antialpha1, Increased SE, decreased SOL, decreased
antiach REM sleep% except with trimipramine
(see text), increased periodic limb
movements in sleep
SSRI: parox- Serotonin reuptake inhibitor Variable effects on sleep continuity with
etine, majority causing sleep fragmentation.
fluoxetine, Also decreased REM sleep% and
citalopram increased REM latency, increased periodic
limb movements in sleep, “prozac” eyes
SNRI: venlafax- 5-HT and norepinephrine Insomnia, decreased REM sleep%, increased
ine and reuptake inhibitor periodic limb movements in sleep
duloxetine
(continued)
34 S. Chowdhuri

Table 2.6 (continued)

Effect on sleep duration, sleep latency and
Drug Mechanism of action sleep architecture
MAOI 5-HT and NE reuptake Decreased SOL, decreased REM sleep%,
blocker, antiAch and H1 increased periodic limb movements in
antagonist sleep, decreased sleep continuity
Quetiapine 5-HT1A, 5-HT2, dopamine (D1 Increased TST, SE, unchanged SOL [182]
and D2), H1 antagonist Increased stage 2 duration @ 2–4 days;
and adrenergic a (alpha) 1 unchanged at 3–4 weeks, unchanged SWS
and a (alpha) 2 receptors and decreased duration in REM sleep @
antagonist [181] 2–4 days, but unchanged @ 3–4 weeks
Quetiapine increased leg movements in sleep
[182]
Olanzapine H1 antagonist, anti-5-HT2, Increased TST, SE and SWS; variable effect
antialpha1, antiAch, on REM; may acutely increase REM
antidopaminergic density
Ziprasidone H1 antagonist, anti-5-HT2, Increased TST, SE and SWS; suppressed
antialpha1, antiAch, REM sleep with prolonged REM latency
antidopaminergic
Risperidone Anti-5-HT2, anti alpha1, Suppressed REM and prolonged REM latency
antidopaminergic
Nonselective H1 antagonist, antiAch Increased sleep efficiency, unchanged SWS
antihista- and REM%, tolerance develops early to
mines (H1) the sedating effect
For annotations, see Table 2.4. See text for other references
AntiAch anticholinergic; H1 histamine-1 receptor; 5-HT serotonin; TCA tricyclic antidepressants;
MAOI monoamine oxidase inhibitor; SSRI selective serotonin reuptake inhibitor; SNRI serotonin
norepinephrine reuptake inhibitor
a
Drug is currently undergoing clinical trials
b
The effectiveness of these drugs on sleep was studied in individuals with major depression

Table 2.7 Drugs that modify SWS and REM sleep percentages
Increase REM Decrease REM Increase SWS Decrease SWS
Bupropion± Benzodiazepines Gabapentin Benzodiazepines
Trazodone± Barbiturates Pregabalin Barbiturates
Sodium oxybate TCA Tiagabine
MAOI Lithium
SSRI Mirtazapine
Venlafaxine Trazodone
Duloxetine Olanzapine
Bupropion± Ziprasidone
Trazodone± Risperidone
Traditional antipsychotics, Sodium oxybate
e.g., Haldol Valerian
Riperidone
Ziprasidone
For annotations, see Tables 2.4 and 2.6; and text; ± variable effect on sleep in different studies.
See references [81, 85, 96, 97, 99]
2 Pharmacology of Sleep 35

Other Antidepressants

Antidepressants with 5HT2, 5HT3, and alpha2 receptor blockade such as mirtazapine
improve sleep continuity and may therefore be used for depressed patients with
insomnia [84, 85]. Bupropion is a dopamine and norepinephrine reuptake inhibitor.
Unlike the antidepressants listed earlier, it may decrease periodic limb movements
and also produce insomnia. The monoamine oxidase inhibitors (MAOI) block
the activity of monoamine oxidase, an enzyme which breaks down serotonin,
norepinephrine, and dopamine. Thus, these drugs raise the brain levels of these
neurotransmitters and produce sleep fragmentation. Side effects of MAOI include
orthostatic hypotension, headache, weight gain, and insomnia. When on MAOI,
ingestion of foods containing the amino acids with tyramine or tyrosine may lead to a
life-threatening hypertensive crisis.

Antipsychotic Agents

Both the traditional and atypical antipsychotics are sedating due to their antagonism
of dopaminergic, histaminergic, serotonergic, a(alpha)1-adrenergic systems [95]
(Table 2.6). There are no consistent effects of the traditional antipsychotics on sleep
architecture in healthy individuals, but overall they increased TST and SE, and
increased REM latency in schizophrenic patients [96]. The atypical antipsychotics
have been evaluated in a nonsystematic fashion in small groups of healthy individu-
als for their effects on sleep [97]. They increased TST and sleep efficiency except for
risperidone that showed minimal effect. Ziprasidone, risperidone, and olanzapine
increased SWS sleep [97, 98]. Risperidone and ziprasidone suppressed REM sleep
and tended to prolong REM latency. Variable effect on REM sleep was noted in
different studies with olanzapine. Olanzapine may increase REM density acutely [96].
Quetiapine increased TST and SE but did not have a lasting effect on REM sleep.
While most of the antipsychotics are sedating, aripiprazole is the least sedating [97].
Periodic limb movements, RLS, and weight gain have been observed with both the
traditional and atypical antipsychotics likely related to their antidopaminergic prop-
erties [97]. There also case reports of nocturnal eating and somnambulism [96].

Other Sedating Drugs

Antihistamines such as diphenhydramine and doxylamine are associated with

subjective drowsiness and reduced sleep latency but tolerance develops within 2 weeks
of use. Valerian is a plant extract with GABA activity that shortens sleep latency
and improves sleep efficiency [99]. Gabapentin has been associated with reduced
periodic leg movements during sleep in patients with restless leg syndrome, with
increased total sleep time, sleep efficiency, and slow wave sleep, and decreased
stage 1 sleep [100]. The mechanism of action of gabapentin on sleep is not clear.
36 S. Chowdhuri

Newer Sedatives Under Development

Almorexant

Orexin/hypocretin stabilizes wakefulness and is implicated in the pathophysiology

of narcolepsy [1]. The administration of an orexin/hypocretin antagonist in animal
models and humans decreased sleep time. Almorexant and other orexin/hypocretin
antagonists are novel drug types under development and undergoing phase II and III
clinical trials in patients with insomnia. Almorexant is an orally active dual OX1
and OX2 receptor antagonist that readily crosses the blood–brain barrier. Preclinical
studies and phase I clinical trials have demonstrated that almorexant decreases
alertness and increases sleep in healthy rats, dogs, and humans when administered
during the active phase of the circadian cycle. In phase I trials, almorexant increased
sleep efficiency (p < 0.001). There was also improved mean SE (85.4 vs. 71.0%),
LPS (36.2 vs. 54.2 min), WASO (40.0 vs. 94.0 min), latency to REM (76.6 vs.
121.9 min), and percentage of REM (19.2 vs. 16.2%) with no effects on next-day
performance [101]. No significant toxicological or safety concerns were noted,
however, concerns for drug safety were recently reported from a phase III trial.
RESTORA 1 (REstore physiological Sleep with The Orexin Receptor antagonist
Almorexant) was a (non-US) multicenter, double-blind, randomized, placebo-
controlled, active reference (zolpidem), parallel-group polysomnography study to
evaluate efficacy and safety of 16-day oral administration of almorexant 200 and
100 mg in adult 709 patients with chronic primary insomnia. RESTORA 1 met its
primary endpoint, with significant superiority of almorexant over placebo on
objective and subjective wake after sleep onset (WASO). Detailed results from this
study are pending. Phase III clinical trials in the USA will be soon underway.

Agomelatine

Agomelatine is a MT1 and MT2 receptor agonist like ramelteon and also has 5-HT2C
receptor antagonist properties. This has allowed it to be used as a novel agent for the
treatment of depression along with an effect on the sleep–wake cycle [102]. Majority
of the published literature focuses on its use as an antidepressant. These studies
observed the positive impact of the drug on sleep in individuals with major
depression. Polysomography findings after treatment with agomelatine showed an
improvement in sleep architecture [103]. There were significant improvements in
sleep efficiency, SWS, and the distribution of delta activity throughout the night, but
no change in the amount or latency of REM sleep. SWS was resynchronized and
distributed to the first sleep cycle of the night. There was a significant increase in the
duration of SWS (stages 3 and 4), from 66 ± 20 min to 80 ± 20 min at 6 weeks
(p < 0.02 compared with baseline) together with an increase in the delta ratio (from
0.88 ± 0.35 to 1.16 ± 0.57 at 6 weeks, p < 0.007). Administration of agomelatine
(50 mg) or placebo for a period of 15 days caused phase advances of an average of
2 Pharmacology of Sleep 37

2 h in the temperature profile as well as in the temporal organization of cortisol

secretion [104], suggesting that agomelatine may also be useful as a chronobiotic
agent. Further studies regarding its effects on sleep are warranted.

Stimulants/Wake-Promoting Drugs

This section discusses amphetamine-like stimulants, modafinil, armodafinil, and

sodium oxybate. In contrast to the sedatives, the wake promoters act via activation of
the noradrenergic, dopaminergic, and/or serotonergic systems. Table 2.8 outlines the
mechanisms, pharmacology, and the FDA-approved indications for these agents.

Amphetamine-Like Substances

Amphetamines act by blocking the reuptake and enhancing the release of norepi-
nephrine, dopamine, and serotonin [105]. Methylphenidate 20 mg reduced REM
sleep, prolonged REM latency, increased sleep latency, and reduced TST [106].
Data on the efficacy of these agents as wake-promoting drugs are limited. Side
effects include headaches, irritability, nervousness or tremors, psychosis, anorexia,
insomnia, gastrointestinal complaints, dyskinesias, and palpitations. Methylphenidate
and dextroamphetamine are controlled substances that are FDA pregnancy category
C drugs. Dextroamphetamine is now approved for treatment of narcolepsy. The
drugs are contraindicated in patients with advanced arteriosclerosis, symptomatic
cardiovascular disease, moderate to severe hypertension, hyperthyroidism, history
of drug abuse, or with administration of MAO inhibitors. A “black box” warning
emphasized that amphetamines have a high potential for abuse.

Modafinil

Modafinil is a nonamphetamine wake-promoting agent that is FDA indicated for the

treatment of excessive daytime sleepiness in narcolepsy, SWSD, and in patients
with obstructive sleep apnea (OSA) with residual daytime sleepiness on adequate
positive airway pressure therapy (PAP) (Table 2.8). The exact mechanism of action
of modafinil is not well understood. Studies have proposed different mechanisms
[107]. Modafinil may act by binding to the dopamine transporter [108], inhibiting
dopamine reuptake and activating dopamine receptors or via activation of histamin-
ergic neurons [109]. Modafinil is effective in hypocretin (orexin) knockout animals
indicating that hypocretin is not needed to mediate its effects [110]. Modafinil selec-
tively activated wake-generating sites in the hypothalamus as displayed by increased
FOS immunoreactivity in the tuberomammillary nucleus and hypocretin neurons of
Table 2.8 Wake-promoting drugs
Mechanism
Drug of action Dose of active drug Side effects PSG/MSLT/MWT Other comments
Amphetamines: Increased monoamine 5–20 mg twice a day Insomnia, restlessness, tachycar- Amphetamines promote Amphetamines are federally
Methamphe- release and 5–30 mg bid or 10 mg SR qam dia, hypertension, dizziness, wakefulness by controlled substance
tamine increased with 10–20 mg qpm diarrhea, psychosis (rare) blocking the reuptake Schedule II drugs.
(Desoxyn®) extracellular Nervousness, insomnia, anorexia, and increasing the Methylphenidate and
Dextroam- dopamine and nausea, palpitations, release of dopamine, dextroamphetamine are
phetamine norepinephrine dizziness, hypertension, norepinephrine, and FDA approved for
(Dexedrine®) availability headache serotonin in the central narcolepsy and ADHD
Methylphenidate Blocks reuptake of 10–30 mg bid, nervous system –this [183]. Often prescribed
(Concerta®, dopamine, or 20 mg SR qam with reduce TST, SWS and as first-line agents for
Ritalin®) norepinephrine and 10–20 mg REM sleep therapy of excessive
serotonin qpm daytime sleepiness in
narcolepsy
Modafinil Exact mechanism is 100–400 mg or Common: headache, nausea, No change in sleep Federally controlled
(Provigil®) not known (see 200 mg bid nervousness, rhinitis, diarrhea, latency, sleep substance Schedule IV
text) Peak concentration: 2–4 h back pain, anxiety, insomnia, architecture. drug. FDA approved use
Reduce dosing in hepatic dizziness, and dyspepsia. Less Improved day time in adults, for excessive
impairment and elderly common: chest pain functioning and sleepiness associated
Drug interactions: reduced hypertension, tachycardia, reduced daytime with narcolepsy, shift
levels of oral contracep- precaution: reports of sleepiness work sleep disorder,
tive, cyclosporine with the Stevens-Johnson Syndrome, obstructive sleep apnea
drug; increased levels of toxic epidermal necrolysis and (as an adjunct to
diazepam, phenytoin and drug rash with eosinophilia adequate PAP use)
propranolol and systemic symptoms,
multiorgan hypersensitivity
reaction, angioedema
Armodafinil Similar to Narcolepsy and OSA: 150 or Common: headache, nausea, No changes in sleep Federally controlled
(Nuvigil®) modafinil 250 mg qam dizziness, and insomnia. Less latency, sleep substance Schedule IV
(R-modafinil) is SWD: 150 mg given daily 1 h common: dyspepsia, efficiency, arousals, drug. Indications are
the longer acting prior to the start of the palpitation, rash, increased WASO, or sleep same as for modafinil
R isomer of work shift liver enzymes staging
modafinil
Sodium oxybate GHB 4.5–9 g nightly at bedtime; Common: headache (22%), Increase in slow-wave Federally controlled
(Xyrem®) receptors 1 recommended starting at nausea (21%), dizziness sleep duration and substance Schedule III
GABAB 4.5 g/night divided into (17%), nasopharyngitis (8%), delta power, and drug
receptors 2 two equal doses, adjusted somnolence (8%), vomiting decrease in REM
up to a maximum of 9 g/ (8%), and urinary inconti- sleep duration and
night in increments of nence (7%) nocturnal increases in
1.5 g/night at 1- to 2-week total sleep time with
intervals sodium oxybate
Reduce the starting dose of Also noted: confusion, depres- 9 g/night. Total NREM FDA approved for
sodium oxybate by sion, sleepwalking, psychosis, sleep increased with excessive daytime
one-half in patients with paranoia, hallucinations, and increase SWS sleepiness and
liver dysfunction agitation, tremor, fall, (43.5 min) and cataplexy in
hypertension decrease in nocturnal narcolepsy
Mechanism by which Absorption is delayed by high Contraindicated with concomitant awakenings [155] NOTE: sodium oxybate
sodium oxybate fat meals. Half life 0.5–1 h, sedative hypnotic agents and appears to increase
inhibits cataplexy is short half-life necessitates alcohol growth hormone
unknown twice-nightly dosing release
Metabolized to water CAUTION: sodium
and carbon dioxide oxybate associated
through Krebs cycle deaths have been noted
oxidation in patients with
obstructive sleep apnea
For annotations, see Table 2.4 and text. MSLT Mean sleep latency test, MWT Maintenance of wakefulness. Test All drugs are pregnancy category C drugs, except sodium
oxybate which is a category B drug.
ADHD attention deficit hyperactivity disorder
40 S. Chowdhuri

the perifornical area [111]. A recent study indicated that modafinil may also act by
opening “gap junctions” between neurons [112].
Modafinil is a compound comprised of two enantiomers, the S-isomer with a
half-life of 3–4 h and the R-isomer with a half-life of approximately 15 h. The
elimination half-life is 10–12 h for single dosing and up to 15 h after multiple
dosing, the maximum concentration is achieved in 2–4 h [113]. It is metabolized in
the liver by the cytochrome P450 system; hence, drug–drug interactions with agents
metabolized via same pathway (Table 2.8) may arise. Recommended dose is 200 mg/
day but doses up to 400 mg/day, in one or two divided doses [113].
Drug efficacy studies: A number of reviews have analyzed data regarding modafinil
efficacy in controlled trials. The reader is referred to these detailed reviews [114,
115]. A recent meta-analysis pooled data from nine randomized double-blind con-
trolled trials [116]. The studies were double blind, placebo controlled with doses of
200–400 mg of modafinil [117–125] including 1,054 patients with narcolepsy with
or without cataplexy with a length of follow-up from 2 to 9 weeks at doses of 200 mg/
day [124, 125], 300 mg/day, [120] and 400 mg/day [124, 125]. Modafinil in compari-
son with placebo significantly decreased excessive daytime sleepiness assessed by
Epworth Sleepiness Scale (ESS) with a weighted mean difference of −2.73 points
(95% CI −3.39, −2.08), improved MSLT (multiple sleep latency test) and MWT
(maintenance of wakefulness test) test results with a weighted mean difference of
1.11 min (95% CI 0.55, 1.66) and 2.82 min (95% CI 2.40, 3.24), respectively. There
was also a decline in the duration of daytime sleepiness and the number of sleep
attacks and naps per day. As expected, there was no effect on cataplexy. Following 9
weeks of treatment with 200 or 400 mg/day dosing, modafinil improved quality of
life on the SF-36 questionnaire [124, 125] and also on a validated narcolepsy specific
questionnaire [126]. Modafinil improved energy, attention, self-esteem, and social
functioning. Performance improved in one study [120] and clinical global impres-
sion (CGI) scale of physician improved [124, 125]. The likelihood of falling asleep
increased after withdrawing modafinil [122]. Modafinil had a similar effect on exces-
sive daytime sleepiness as sodium oxybate [119] with no difference in the change in
ESS scores and mean sleep latency (MSL) on MWT. Nausea was noted more often
with sodium oxybate. There are no randomized controlled trials comparing modafinil
with methylphenidate or other amphetamine-like stimulants. While sleepiness
recurred both subjectively (ESS) and objectively (MWT) upon discontinuation of the
drug, withdrawal symptoms such as those noted with amphetamines were absent,
suggesting that modafinil is not “addictive” and has a lower potential for abuse [113].
Modafinil 400 mg, taken once daily or as a split dose in the morning and at midday,
was significantly better at promoting wakefulness throughout the entire day than
modafinil 200 mg taken once daily in the morning [127]. However, psychiatric alter-
ations have been noted in patients under combined treatment with sodium oxybate
and modafinil [128]. Patients should be monitored for psychiatric alterations in nar-
colepsy–cataplexy patients treated with sodium oxybate and CNS stimulant drugs.
In addition to narcolepsy, there is good evidence that modafinil is effective in
reducing residual daytime sleepiness in patients with OSA despite adequate therapy
2 Pharmacology of Sleep 41

with PAP [129–131], with an improvement in quality of life. OSA patients should
be told that they must continue to take their previously prescribed CPAP treatment
for OSA while on the drug. Modafinil also decreased frequency and duration of
lapses of attention in a clinical trial of 209 patients with SWSD who received either
200 mg of modafinil before the start of each shift [133]. There were fewer accidents
or near accidents, however, there was residual sleepiness [133].
Table 2.8 provides the indications, recommended dosing, and potential adverse
effects of modafinil and armodafinil. In a compilation of data from six randomized,
double-blind, placebo-controlled studies, modafinil has a good safety profile [134]
and is well tolerated in the treatment of excessive sleepiness narcolepsy, shift
work disorder, and sleepiness related to OSA. It did not affect the sleep architecture
by polysomnography or any cardiovascular parameters (blood pressure or heart
rate). Polysomnography showed no notable changes in sleep architecture mea-
sures, TST, sleep efficiency,%REM sleep, latency to N1, REM latency, or arousals
on polysomnography. In shift work studies, the increase in MSL objectively was
small (approximately, 2 min at both 200 mg and 400 mg); however, patients’ subjective
assessment of sleepiness was much improved, with a reduction in the ESS score by
approximately 4 points at the 200 mg dosage and 6 points at 400 mg. Clinicians’
subjective assessment of overall clinical improvement was also demonstrated
by CGI scales.
While modafinil is FDA approved for the three listed indications, it has been
studied (off-label) in various other conditions that produce hypersomnia including
traumatic brain injury [135], idiopathic hypersomnia [136], multiple sclerosis [137],
and fibromyalgia as well as for alleviation of fatigue [138].

Armodafinil

Armodafinil, the R-enantiomer of modafinil, has a longer half-life of 15 h and is

dosed once daily in the AM. Armodafinil has been shown to increase MSL. On
30-min MWT, armodafinil resulted in a small (2.3 min) but statistically significant
increase from baseline in MSL, compared to placebo on the first four MWT sessions
(0900–1500) compared with placebo in OSA patients with residual EDS. Armodafinil
also reduced fatigue [139, 140]. Armodafinil also significantly increased the MWT
MSL in narcoleptic patients [141]. In patients with excessive sleepiness associated
with chronic SWSD, armodafinil significantly improved wakefulness during scheduled
night work, raising mean nighttime sleep latency, from 2.3 (1.6) minutes at baseline
to 5.3 (5.0) minutes, over a period of 12 weeks [142]. The effectiveness of armodafinil
lasted after long-term use (³than 12 month) and well tolerated in open-label trials in
patients with excessive sleepiness associated with treated OSA, SWSD, or narcolepsy
[142, 143, 144]. Armodafinil was also effective in reducing sleepiness due to jet lag fol-
lowing eastward travel through 6 time zones [145]. The drug has been effective in the
setting of fatigue related to fibromyalgia [146].
42 S. Chowdhuri

Neither modafinil nor armodafinil is FDA approved for use in pediatric patients for
any indication. These drugs induce cytochrome P450 enzyme, leading to reduced
levels of oral contraceptive. Hence, female patients should use another form of con-
traception while on these medications.

Sodium Oxybate

Sodium oxybate is the sodium salt of the recreational drug, gamma-hydroxybutyric

acid (GHB). It is FDA approved for the treatment of cataplexy and excessive
daytime sleepiness in patients with narcolepsy but given its abuse potential and
CNS depressant effect, the drug is available only through a centralized pharmacy.
Oral sodium oxybate is rapidly absorbed with a high first-pass metabolism; absorp-
tion is slowed by fatty meals, and hence, the drug should be taken a few hours after
a meal [147]. Sodium oxybate is metabolized to water and carbon dioxide through
Krebs cycle oxidation. It is eliminated rapidly from the circulation in 20–53 min,
necessitating twice-nightly administration, taken at bedtime while in bed and again
2.5–4 h later [149].
Drug efficacy: While the exact mechanism of action of sodium oxybate is not known,
it probably acts by binding to GHB and GABAB receptors [148]. In healthy volun-
teers and in patients with narcolepsy, the drug improved sleep continuity, thereby
improving daytime sleepiness. There were dose-related increases in SWS duration
and delta power, increases in sleep latency, and decreases in nocturnal awakenings in
patients with narcolepsy with cataplexy. REM-sleep duration increased initially at
lower doses, but then decreased in a dose-related manner [150]. The mechanism of
the anticataplectic action is unknown. In a randomized, double-blind, placebo-con-
trolled trial, sodium oxybate 6–9 g/night, significantly reduced the frequency of cata-
plexy attacks in patients with narcolepsy with cataplexy after 4 weeks of therapy, in
a dose-related manner. The ESS was reduced at all doses, becoming significant at the
9-g dose (p = 0.0001). The CGI scores increased, and the frequency of sleep attacks
and nighttime awakenings decreased in a dose-related fashion [151]. Additionally, a
12-month, open-label, extension trial in the same patient cohort, demonstrated that
the positive benefits on cataplexy and daytime sleepiness were maintained at the end
of the study period with few adverse effects. Of note, 87% of patients who entered
the trial were on concomitant stimulant mediations. The most common adverse
events were headache, nausea, viral infection, dizziness, pain, enuresis, and somno-
lence [151, 152]. There was a significant median increase of >10 min in the MWT
after therapy with 9 g of sodium oxybate in adults with narcolepsy with cataplexy.
Nightly doses of 4.5, 6, and 9 g sodium oxybate for 8 weeks resulted in statisti-
cally significant median decreases in weekly cataplexy attacks of 57.0, 65.0, and
84.7%, respectively [153]. Sodium oxybate as monotherapy or in addition to the
stimulant modafinil induced 5 or 26% increases in mean sleep onset latency on MWT.
Sodium oxybate and modafinil produced additive effects when used together for the
2 Pharmacology of Sleep 43

treatment of excessive daytime sleepiness in narcolepsy [119]. After 8 weeks, sig-

nificant changes in sleep architecture among patients receiving sodium oxybate and
sodium oxybate/modafinil included a median increase in Stage 3 and 4 sleep (43.5
and 24.25 min, respectively) and delta power and a median decrease in nocturnal
awakenings (6.0 and 9.5, respectively) [155]. There was a significant improvement
in the functional status measure of quality of life using the Functional Outcomes of
Sleep Questionnaire [156].
Side effects: Sodium oxybate was well tolerated and the most common adverse
events were headache, dizziness, nausea, vomiting, pain, enuresis, somnolence, and
nasopharyngitis [152]. Sleepwalking was reported in 4% of 717 patients treated in
clinical trials with sodium oxybate [153]. Although not systematically evaluated in
controlled clinical trials, no acute withdrawal symptoms were observed after 2
weeks of discontinuation following an average of 21 months of therapy (range:
7–44 months). The abrupt cessation of sodium oxybate therapy resulted in a significant
increase in the number of cataplexy attacks, however, the cataplexy attacks returned
gradually and there was no acute rebound in cataplexy [157].
Sodium oxybate is a Schedule III drug. GHB (parent drug) abuse at high doses
has been associated with CNS depression, bradycardia, hypotension, seizure, respi-
ratory depression, depressed level of consciousness, with instances of coma and
death [158]. Thus, strict risk-management strategies and rigorous adherence to the
up-titration schedule are needed. Synergistic interactions of GHB with alcohol or
other CNW depressants may increase the risk of intoxication or overdose. There is
limited information about efficacy and safety in elderly populations and in patients
less than 16 years of age. Daily sodium intake should be considered in patients
with heart failure, hypertension, or compromised renal function. Patients with
compromised liver function should have their starting dose decreased by one half
and response to dose increments monitored closely [148, 185].

Drugs of Abuse

Effects of illicit drugs on sleep can be studied under two main headings, effects
on sleep after acute or chronic exposure and effects on sleep after withdrawal or
discontinuation of the drug. Alcohol is commonly self-administered as a sedative to
treat sleep-onset insomnia. It is sedating via binding to the GABA receptor. In 17
young male adults, a single acute dose of alcohol prior to bedtime produced a
significant decrease in percent stage REM during the first half of the night, with a
reduction in the average length of the first REM episode from 18.6 min during
baseline to 12.1 min on the alcohol night (p < 0.05) [159]. During the second half of
the alcohol night, there was a significant “rebound” increase in REM sleep with a
concomitant reduction in stage 2 sleep. Thus, alcohol apparently affected the distri-
bution of REM sleep. Alcohol did not cause a significant alteration in the total
amount of REM sleep in this study [159]. Table 2.9 lists the mechanisms of action
of alcohol and illicit drugs of use and their effects on sleep [159–171].
 44

Table 2.9 Drugs of abuse and their effects on sleep

Drug Site of action Effect of drug administration Effect of drug withdrawal/abstinence
Alcohol [159] GABA receptor agonist First portion of the night: acute effect Second portion of the night: after alcohol is
of alcohol decreases REM% with metabolized, there is significant “rebound” in
reduction in average length of the REM sleep with reduction in stage 2 sleep. REM
first REM episode sleep behavior disorder may appear following
chronic alcohol use.
Cocaine [161] Inhibition of presynaptic PSG: longer sleep latency, reduced total Significantly reduced TST, SE, prolonged SOL,
dopamine transporters, sleep time, and suppression of REM increased REM percentage, and reduced REM
increased dopamine sleep after acute drug administration latency (increased dreaming) followed by
availability insomnia and REM disturbance.
3,4-methylenedioxy Rapid release of serotonin, Animal studies show increased wakeful- Persistent effect of MDMA after abstinence: there
methamphetamine binds to serotonin 5-HT2 ness after acute use, associated with was reduced stage 2, TST, increased stage 1,
(MDMA) [162] receptors, rapid circadian clock abnormalities [160] reduced REM latency, REM suppression,
(Ecstasy) dopamine release possible increased sleep efficiency and SWS
[163, 164].
Cannabis (D-9- Cannabinoid CB1- THC increases wakefulness and Sleep difficulty and strange dreams are frequently
tetrahydrocannabinol receptors [160] decreases total REM sleep and REM reported effects of marijuana withdrawal with
is the active density, variable effect on SWS, but increased sleep onset latency and wakefulness
compound) [160] may increase REM sleep in chronic after sleep. There is reduced SWS and increased
users [165–168] REM sleep [165–167].
Opiates [170, 171] Opioid receptors 12 Dose related decreased in TST, SWS Withdrawal after chronic opioid use is associated
and REM sleep. Increased arousals with initial insomnia and decreased REM; during
and wakefulness after sleep onset protracted abstinence phase, TST significantly
[169] in some studies no change in increases with rebound SWS and REM sleep
SWS. Chronic use is associated with between 13 and 22 weeks following withdrawal
central apneas with ataxic breathing of opioids [171]
[170, 171]
For annotations, see Table 2.4
S. Chowdhuri
2 Pharmacology of Sleep 45

New Drugs Under Development

Several agents, both stimulants and sedatives, are in development for the treatment
of sleep disorders. Potential sedating drugs in development include tiagabine, partial
GABA agonists, new M1–M2 agonists, and other selective serotonin subtype receptor
antagonists (5HT2A). Drugs that antagonize the activating histaminergic system are
also sedating [172–174]. There is also great interest and potential for developing
novel wake-promoting drugs, such as hypocretin agonists and other hypocretin-
based therapy. However, a major limitation is that hypocretin-1 does not cross the
blood–brain barrier and, therefore, cannot reach the CNS [175]. Thyrotropin-releasing
hormone (TRH) agonists increase alertness and are wake promoting as well as anti-
cataplectic in the narcoleptic canine model [176]. These can be developed as potential
drugs for narcolepsy. Additionally, further studies investigating the role and efficacy
of almorexant, agomelatine, and histamine antagonists will allow us to add these to
our armamentarium of drugs that treat sleep disorders.

Summary of Keypoints

• Sleep- and wake-promoting drugs act by modulation of key sleep- and wake-
promoting neurotransmitters and their corresponding receptors sites.
• GABA (g(gamma)-amino butyric acid) is an important sleep-promoting neu-
rotransmitter. Potentiation of GABA activity produces sedation. Benzodiazepines
and NBRAs promote sleep by binding to the GABAA receptor and modulating
the flow of chloride ions into the cell, thereby inhibiting neuronal activity.
Depending on the half-life, these drugs improve sleep latency, sleep mainte-
nance, total sleep time, and overall sleep quality. Unlike the benzodiazepines, the
NBRAs do not alter the REM or SWS percentages.
• Ramelteon and tasimelteon reduce sleep latency by binding selectivity to the MT1
and MT2 receptors in the SCN, without producing changes in REM or SWS.
• One needs to be aware of the potential side effects, contraindications, and drug
interactions of these agents. Sedatives can potentially have a “hang-over effect”
the next day and may be associated with complex behaviors during sleep.
• A number of antidepressants and antipsychotics have been used “off-label” as
sedatives. Low dose doxepin is now FDA approved as the first antidepressant with
an indication for the treatment of sleep maintenance insomnia. The high specific-
ity and affinity of doxepin to the histamine H(1) receptor allows it to be a good
sedative at low doses without concomitant major anticholinergic side effects.
• Almorexant and other orexin/hypocretin antagonists are novel drug types under
development and undergoing phase II and III clinical trials in patients with
insomnia.
• Amphetamine-like stimulants, as well as modafinil and armodafinil are wake pro-
moters that act via activation of the noradrenergic, dopaminergic, serotonergic, and/or
histaminergic systems. These drugs are prescribed for patients with narcolepsy.
46 S. Chowdhuri

• Modafinil and armodafinil are also FDA approved for reducing residual daytime
sleepiness in patients with OSA despite adequate therapy with PAP and for
patients with SWSD.
• Sodium oxybate increases SWS, reduces nocturnal awakenings, and promotes
wakefulness probably via activity at the GABAB or GHB receptor sites. It is
approved for the treatment of cataplexy and excessive daytime sleepiness in
patients with narcolepsy but given its abuse potential and CNS depressant effect,
the drug is available only through a centralized pharmacy. Strict risk-management
strategies and rigorous adherence to the up-titration schedule are recommended.
• Several agents, both stimulants and sedatives, are in development for the treatment
of sleep disorders. These include partial GABA agonists, new M1–M2 agonists,
histamine antagonists, other selective serotonin subtype receptor antagonists
(5HT2A), hypocretin receptor antagonists, among others.

Acknowledgement Career Development Award from the Department of Veterans Affairs.

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2 Pharmacology of Sleep 53

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Chapter 3
Obstructive Sleep Apnea: Diagnosis with
Polysomnography and Portable Monitors

Chunbai Zhang, Stefanos N. Kales, and Atul Malhotra

Keywords Sleep • Apnea • Diagnosis • Lung • Monitoring • Breathing

Introduction

Definition of Obstructive Sleep Apnea (OSA): OSA is the leading cause of referral
to sleep laboratories worldwide, accounting for at least 75–80% of diagnoses [1, 2].
In the last few decades, there have been considerable advances in knowledge regarding
the underlying mechanisms, diagnostic approaches, treatment options, and the
impact of OSA on personal as well as public health of OSA since the disease
terminology was first coined. The current definitions of sleep apnea are not uniform,
but most of them attempt to characterize the frequency of sleep-disordered breathing
events (e.g., AHI “Apnea–Hypopnea Index” or RDI “Respiratory Disturbance
Index”) along with the severity (e.g., oxygen desaturation) of each event (e.g.,
complete (apnea) and partial (hypopnea) cessation of breathing during sleep) [2].
By convention, an apnea is defined as greater than 90% reduction of air flow for at
least 10 s [2–5]. A hypopnea is defined as a reduction in airflow that is followed by
an arousal from sleep or a decrease in oxyhemoglobin saturation. While AHI is the
most commonly used parameter to assess sleep apnea severity, several additional
measures of sleep such as the degree of nocturnal oxyhemoglobin desaturation and
the amount of carbon dioxide exhaled have been used to characterize disease severity
in clinical and research settings [6, 7].
The mechanisms of sleep-disordered breathing are complex, but can involve
either obstruction of the upper airways (OSA) in the presence of intact respiratory

C. Zhang • S.N. Kales • A. Malhotra (*)

Sleep Disorders Program, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 55
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_3,
© Springer Science+Business Media, LLC 2012
56 C. Zhang et al.

drive; the absence of ventilatory drive (CSA or central sleep apnea) in the presence
of a patent airway; or mixed apnea, which has features of both OSA and CSA [8].
Pure CSA is much less common than OSA in the general population; CSA occurs
most often in individuals with congestive heart failure (CHF) or occasionally with
neurological compromise or chronic narcotic intake.
Patients with OSA can frequently experience sleep fragmentation, daytime
somnolence, or suboptimal psychomotor function. Untreated OSA can also lead to
common comorbidities such as hypertension, diabetes, stroke, and depression.
Individuals with moderate and severe OSA have increased risks for hypertension,
cerebrovascular accident (CVA), cardiovascular diseases, diabetes mellitus, depression,
road traffic crashes, poor performance in school and work, and decreased productivity
in the workplace [9–15].

Prevalence and Epidemiology

The estimated prevalence of symptomatic OSA in the United States in early 1990s
by Young et al. was 4% among adult men and 2% among adult women [16]. Since
then, prevalence data from other countries have emerged. The prevalence of OSA
associated with daytime sleepiness is 3–7% in adult men and 2–5% in adult women
[2, 17]. Subgroups of those populations have higher prevalence, including persons
with older age, male gender, and obesity. Though diagnostic methodologies vary,
most available epidemiologic data on prevalence of OSA confirm Young’s finding
across the globe [16, 18–22]. Interestingly, the prevalence of OSA in developing
countries such as India and China is on the same order of magnitude as that in the
developed countries, despite less obesity. Therefore, OSA is not only a disease of
more developed countries, but a common disease worldwide. Additionally, there are
huge and growing individual and public health costs associated with OSA, whether
from lost productivity at work places, motor vehicle accidents from drowsy driving,
or the cardiovascular and metabolic comorbidities of OSA. Because the obesity
epidemic is spreading worldwide, we can only imagine an increasingly higher
prevalence of OSA in the twenty-first century [23].

Risk Factor

Despite substantial research on OSA in the past several decades, OSA remains under-
diagnosed [24]. This is due in part by the lack of awareness of the disease by patients
as well as the general public, and insufficient clinical suspicion on the part of physi-
cians. Therefore, it is important for clinicians to gain proper knowledge of OSA risk
factors, so that timely diagnoses can be made and treatment can be initiated.
OSA risk factors include obesity, older age, male gender, postmenopausal status,
Asian/African American races, tobacco, and alcohol use [5, 25]. Studies have shown
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 57

that up to 70% of men and 56% of women between age 65 and 99 year have some
form of OSA [26]. The mechanisms for age-related OSA include deposition of
adipose tissue in the parapharyngeal area and anatomical changes surrounding the
pharynx [27, 28]. Disease prevalence for OSA is relatively low among premeno-
pausal women and increases postmenopausally [29]. Obesity is the single most treat-
able factor predictive of OSA. Data collected in Sleep Heart Health Study (SHHS)
have shown that moderate and severe OSA is independently associated with BMI,
neck circumference, as well as waist circumference. Individuals with OSA have
significantly more visceral distribution of fat than central fat after controlling for
BMI. Visceral fat is significantly correlated with AHI [30]. Waist–hip ratio has also
been shown in some studies to be more predictive of severe OSA than obesity in
general [31]. Only 10–15% of the population with diagnosis of OSA have body mass
index (BMI) less than 25 kg/m2 [32]. Individuals with large neck circumferences
(men >17 in., women >16 in.) should raise the clinician’s suspicion for OSA.
There are multiple theories as to why OSA prevalence in women is lower than
that in men. One of them is that male bed partners of women are less likely to report
bedtime symptoms of OSA than the female bed partners of men. Women with OSA
also tend to have less “classic” daytime symptoms of OSA; instead of reporting
daytime sleepiness they may report fatigue and lack of energy. Lastly, women have
different anatomical and functional properties of their upper airways and differences
in control of breathing. Thus, both diagnostic biases and biological factors contribute
to the gender imbalance in sleep apnea prevalence.
Among different races, obesity plays a varying degree of importance. Middle-aged
(age 25–65 years) African Americans have similar disease prevalence than the other
racial groups, but adult African Americans younger than 25 years or older than 65
years have a higher prevalence than the others [29, 33]. Among the East Asian
population, though the prevalence of obesity is less than the whites, the prevalence
of OSA is not less than that in the West. Therefore, the relationship between obesity
and OSA is less clear-cut among Asians. However, differences in adipose tissue
distribution (i.e., peripheral vs. visceral) may play a more significant role in Asians [34].
Additionally, craniofacial profiles such as crowded posterior oropharynx, shorter
cranial base, and more acute cranial base flexure also seem to be important in patho-
genesis of OSA among nonobese populations [35, 36].

Clinical History

A sleep history looking for OSA should be obtained either as a routine health
maintenance evaluation, part of an evaluation for potential OSA in a symptomatic
person, a comprehensive evaluation of those at high risk for OSA, and as a part of a
screen for sleep disorders in commercial drivers, other transportation operators and
persons involved in safety-sensitive work. A good sleep history should address both
sleep and wakefulness. Because individuals with OSA often disrupt their bed partners’ sleep,
bed partners should be encouraged to participate in this part of the evaluation process.
58 C. Zhang et al.

Table 3.1 Five questions to screen patients for obstructive sleep

apnea (OSA)
Question 1 “Do you have trouble falling asleep or maintaining
asleep at night?”
Question 2 “Have you ever been told that you snore during
sleep?”
Question 3 “Have you ever woken up choking or gasping for air
when you are asleep?”
Question 4 “Has anyone ever witnessed you stop breathing
during sleep?”
Question 5 “Do you have trouble staying awake during the day?”
(Epworth sleepiness score questionnaire)

Loud snoring, awakenings due to choking and/or gasping, and witnessed apneic
episodes during sleep are common symptoms reported by OSA patients or their bed
partners [37, 38]. OSA can make falling asleep and maintaining sleep difficult [39].
Excessive daytime sleepiness (EDS) is a common complaint, although many patients
do not report sleepiness per se. For an individual with OSA, EDS most likely will
persist even after adequate amount of total sleep time (TST) is achieved. The
Epworth Sleepiness Scale (ESS), a self-reported score combining a series of answers
for likelihood of dozing off in eight different scenarios [40]. An ESS of greater than
12 (out of 24) is usually considered “sleepy.” Though subjective, ESS is frequently
used to quantify EDS and is useful as a reference scale for assessing future treatment
effectiveness. Questions on general sleep history such as TST, sleep fragmentation,
sleep maintenance, as well as questions related to insomnia (difficulty falling asleep
or going back to sleep) should also be asked to generate a differential diagnosis.
Lack of concentration and/or cognitive abilities, decreased libido, risk of motor
vehicle accidents, mood disorders, morning headaches, and dry mouth are other
common complaints in OSA patients. History of common comorbidities such as
hypertension, stroke, myocardial infarction, cor pulmonale, and arrhythmia should
also be obtained. In pediatric populations, the complaint of excessive sleepiness is
often replaced by hyperactivity, attention deficit, and mouth breathing. OSA is more
frequently present among children of OSA subjects, suggesting the role of genetic
factors in OSA. Table 3.1 lists questions that a healthcare provider should ask of an
individual suspected of having OSA.
Taking a medical history from certain populations among whom symptoms and
signs of OSA may affect their employment status may be challenging. For example,
unlike the sleep clinic setting where patients are seeking diagnosis and treatment for
sleep difficulties, it is common for commercial vehicle drivers, pilots, and train
operators to avoid an OSA diagnosis because of its economic and occupational
implications. Thus, relying on self-reported symptoms by commercial drivers for
screening for OSA has a very low yield in these occupational settings [41–44].
These groups often do not report any symptoms [42, 44]. Furthermore, drivers with
previously diagnosed OSA initially have been reported to deny the presence of a
sleep disorder until they are told that based on screening criteria they are required to
obtain a sleep study. A 2006 study in Israel showed 78% of its commercial drivers
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 59

Table 3.2 Common risk factors of obstructive sleep apnea (OSA)

Anthropometric measures BMI >28 kg/m2, neck circumference >17 in. (43 cm) for men,
or >16 in.(41 cm) for women
Physical exam Retrognathia, high modified mallampati score (III/IV), large
tonsils (>2), macroglossia
Age Age 35 or greater
Ethnicity Asian, African American, Hispanic ethnicities
Gender Male gender
Hormone Postmenopausal status in women
Habits Alcohol, tobacco

with BMI greater or equal to 32 kg/m2 had polysomnography (PSG)-confirmed

OSA and almost half had objectively confirmed EDS as measured by a multiple
sleep latency test (MSLT), but 100% of the affected drivers denied symptoms of
OSA or EDS [41]. Likewise, most OSA-affected commercial motor vehicle (CMV)
operators report very low ESS score at driver certifications exams (range 3–4 or 2–5
out of 24), which are markedly lower than average ESS scores among college and
medical students (range 7–8) [40–42]. Therefore, at the present time, examiners
must rely primarily upon anthropometric and other objective criteria when evaluating
transportation operators.
A summary statement from the Joint Task Force (JTF) of American College of
Occupational and Environmental Medicine/American College of Chest Physicians/
National Sleep Foundation of screening criteria for OSA among CMV operators
was published in the journal Chest in 2006 [45]. The statement recommends a
3-month maximum certification, pending OSA evaluation, for the CMV operator if
the operator falls into any one of the five major categories. Of note, the only objectively
measurable major category in the JTF statement is the subject’s anthropometric
characteristics and blood pressure measured during the office visit. Therefore, in the
setting of occupational certification, the suspicion for OSA should be elevated with
or without a clear subjective reporting of symptoms of OSA (i.e., EDS). Timely
referral for an OSA evaluation is warranted, if the examinee seeking certification
has two of the following three objectives measurements in clinic:
1. BMI >35 kg/m2
2. Neck circumference >17 in. in men or 16> in. in women
3. Hypertension
Patients with first-degree relatives with OSA are more likely to have OSA than
those without first-degree relatives with OSA. Additionally, multiple medical
conditions have been associated with OSA. In the field of endocrine disorders, type
2 diabetes, polycystic ovary syndrome (PCOS), and hypothyroidism are known to
be associated with OSA. Congenital diseases such as Down’s syndrome or micro-
cephaly are associated with OSA [46]. Pregnant women can present with OSA as
gestational weight gain progresses. Occasionally, rare anatomical abnormalities of
the airway such as Eagle Syndrome can cause OSA. Table 3.2 illustrates common
risk factors for OSA.
60 C. Zhang et al.

Physical Exam

Vital signs can frequently reveal hypertension in people with OSA. Neck circumference
should be documented as it is an important anthropometric measurement. Obesity
(BMI of ³30 kg/m2) is probably the most common finding among OSA patients.
The rest of the physical exam should include head and neck, airway or respiratory,
cardiac, neurologic exams. The head and neck exam of an OSA patient can present
with crowded posterior pharyngeal space (i.e., modified Mallampati III or IV), large
tongue with teeth mark (macroglossia), tonsillar hypertrophy, dental malocclusion
(class II), retracted mandible relative to the maxilla (retrognathism or micrognathism),
or deviated nasal septum. In children with OSA, hypertrophied adenoids or tonsils
are common, and children often compensate by becoming obligatory mouth breathers
[46]. Nasopharyngeal fiber scope can be used in office to evaluate for the shape and
size of the retropalatal/retroglossal airway, though there is no currently available
evidence-based guidelines using this as a diagnostic tool. Internal jugular venous
distension and peripheral edema should be assessed as part of the heart exam.
Cardiac auscultation and pulse palpation can be helpful, particularly given the
known association between atrial fibrillation and sleep apnea. Neurological exami-
nation should focus on muscle strength and presence of any focal deficits, since
neuromuscular disease can present with sleep apnea and/or hypoventilation.

Diagnosis of OSA

There are currently two major methods to diagnose OSA: full in-lab PSG and por-
table monitoring (PM) or Limited-Channel Testing (LCT) device. There is much
ongoing debate as to the utility of each diagnostic tool. In general, PSG offers more
thorough measurements of various aspects of sleep, but it is time consuming, expen-
sive, and performed outside the home. PM offers convenience to patients, but PM is
limited by its reduced sensitivity, specificity, and measured information. Patient
history and physical exam are key determinants for diagnostic route. Due to financial
considerations, PM is becoming increasingly common in the USA and has been used
with reasonable success worldwide. There are four types of PMs Type I–IV, in the
order of decreasing measurements of sleep and respiratory variables (see Table 3.3).

Overnight Polysomnography (PSG)

The current gold standard test for assessing the severity of OSA is in-laboratory,
technician-monitored PSG. A Full PSG (or type I monitor) has been performed
since the 1960s [47]. The initial uses of PSG were to assess sleep physiology in
normal individuals and those with various neurologic or sleep disorders such as
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 61

Table 3.3 Summary characteristics of polysomnogram (type I) and portable monitor (type II–IV)
Type I PSG Type II PSG Type III PSG Type IV PSG
Monitoring personnel Yes No No No
Oximetry Yes Yes Yes Yes
Respiratory effort Yes Yes Yes No
Air flow Yes Yes Yes No
Body positions Yes Yes/No Yes/No No
EMG-AT Yes Yes No No
EEG Yes Yes No No
ECG-heart rate Yes Yes Yes No
EOG Yes Yes No No
Surface EMG Yes Yes No No
Video recording Yes/No No No No
Sound recording Yes/No No No No
Minimum number of channels 14–16 ³7 ³4 ³3
for CMS* reimbursement

seizures, insomnia, narcolepsy, periodic limb movement, and the parasomnias, as

well as to examine the effect of hypnotics and other drugs on sleep. The pulmonary
components of the PSG were added later as OSA was becoming increasingly appre-
ciated in the 1970s.
PSG, which is usually performed as an overnight study, typically assesses physi-
ological parameters by recording sleep–wake stage, heart rhythm, skeletal muscle
activities, respiratory patterns, sound of snoring, and oxygen saturation. Each of the
above respective components is monitored by electroencephalogram (EEG), electro-
oculogram (EOG) or eye movement, heart rate and rhythm (ECG), electromyogram
(EMG) of skeletal muscle activity (usually at the chin and tibialis anterior), respira-
tory effort, snoring (microphone), respiratory air flow, thermistor, and pulse oximetry.
Nasal pressure technology is also commonly used to detect subtle respiratory events
since it has been shown to be more sensitive than standard thermistor. However, the
specificity of nasal pressure has been less well studied, i.e., the consequences of
these subtle events (which are not observed in the thermistor) are unclear [48–51].
Occasionally, sleep studies are done at different times of the day, depending on the
suspected symptoms of the subjects (circadian rhythm disorder, etc.).
The definition of OSA currently involves the measured AHI, the average number
of apnea and hypopnea episodes over an hour. RDI has also been used as an alternative
scale for those measures. We can think of AHI as a subset of RDI, as the definition of
RDI is less strict than AHI. During a full overnight PSG, an apnea is defined by
AASM as cessation (more than 90% reduction) of air movement lasting 10 or more
seconds [3]. As stated previously, the distinction between RDI and AHI is related to
“respiratory effort related arousals” (RERA), which are subtle hypopneas. These
RERAs are included in RDI but not in AHI. Apnea can be distinguished from hypopnea
via a thermistor in PSGs, although the consequences of hypopneas vs. apneas are
generally felt to be similar. While the definition of apnea has been less debated, the defi-
nition of hypopnea is far from settled [3]. The ideal hypopnea definition is unknown.
62 C. Zhang et al.

Table 3.4 Commonly used PSG criteria for scoring hypopnea [3]
Criteria names Definitions of hypopnea (at least one of the followings)
“Chicago criteria” Reduction of airflow ³50%
Reduction of airflow <50% and oxyhemoglobin
desaturation >3%
Reduction of airflow <50% and EEG evidence of arousal
AASM recommended or “medicare Reduction of nasal pressure ³30%
criteria” Oxyhemoglobin desaturation ³4%
AASM alternative Reduction of nasal pressure ³50% and oxyhemoglobin
desaturation ³3%
Reduction of nasal pressure signal ³50% and EEG
evidence of arousal

There are historically at least three different criteria to score hypopneas: the AASM
recommended criteria, and AASM alternative criteria and the “Chicago Criteria” (see
Table 3.4).
The “Chicago Criteria” was the 1999 version of the AASM recommended criteria
for hypopnea. These criteria were designed mainly for clinical research rather than
clinical practice. The Chicago Criteria defines hypopnea as having one of the
following three features:
1. Reduction of airflow (by thermistor) ³50%
2. Reduction of airflow (by thermistor) <50% and oxyhemoglobin desaturation >3%
3. Reduction of airflow (by thermistor) <50% and EEG evidence of arousal
Nasal pressure was early in development at the time of Chicago criteria and was
suggested but not strongly recommended. The lack of hypopnea criteria for clinical
practice was further addressed by AASM in 2001. Via the Clinical Practices Review
Committee, AASM defined hypopnea as having at least 30% reduction of airflow
lasting at least 10 s, and with 4% reduction in oxyhemoglobin saturation. Since
then, the 2001 AASM definition has been adopted by Center for Medicare and
Medicaid Services (CMS) as its criteria for AHI scoring. However, the 2007 Manual
for Scoring of Sleep and Associated Events published by AASM introduced only
two definitions: “recommended” and “alternative” [3]. The AASM Recommended
Criteria is the same as the desaturation-based Medicare criteria, i.e., with no importance
placed on arousal from sleep:
1. Reduction of nasal pressure signal ³30% and oxygen desaturation ³4%
The Alternative Criteria by AASM defines hypopnea as one of the following two
features:
1. Reduction of nasal pressure signal ³50% and oxygen desaturation ³3%
2. Reduction of nasal pressure signal ³50% and associated arousal
A common obstacle in communications between sleep specialists and primary
care physicians (PCPs) is that sleep reports often do not specify which criteria the
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 63

sleep lab has adopted as a standard for scoring OSA [52, 53]. The same obstacle is
magnified further in the case of diagnostic interpretation of OSA using PMs.
Therefore, any sleep report should include not only the calculated AHI or RDI, but
also an explanation of the criteria used for scoring.
The severity of sleep apnea is typically assessed by AHI, but AHI correlates only
loosely with EDS and other outcomes [14, 54]. Different parameters measured by a
sleep study are predictive of various outcomes of OSA [55]. For example, the degree
of oxyhemoglobin desaturation threshold may vary depending on the clinical or
research outcome of interests (i.e., hypertension vs. insulin resistance vs. memory
consolidation). Additional markers have been suggested as risk factors for disease
severity; for example, the degree of nocturnal hypoxemia and the frequency of
arousal from sleep. Therefore, when discussing sleep study findings, it is imperative
for clinicians to integrate patient’s initial chief compliant, unique history, risk factor,
and life style into the assessment. In addition, further data are required regarding
which disease indices have the best predictive value for various outcome measures.
The limitations of in-lab PSG include the “first-night” effect where sleep is less
than usual due to being in a foreign environment, night-to-night variability of the
findings, effects of sleep position (which may be different in home, with a bed partner),
and the effects of certain medications (i.e., selective serotonin receptor inhibitors,
benzodiazepines, hypnotics/alcohol, and stimulants). In-house PSG is quite labor
intensive, requiring oversight by a skilled sleep technician. However, in-lab PSG
remains the gold standard for diagnosis of OSA given the reliability and quantity of
the data provided.

Split Night Study (Diagnosis Combined with Titration)

Frequently a “split-night” study can be done during a full in-laboratory PSG. In a

“split-night” study, an initial impression of the severity of OSA undergoes a “real-
time” assessment by a supervising technician. If the patient qualifies for moderate or
severe OSA during the first half of the overnight study, a titration study is initiated in
the second half of the night to determine an appropriate positive airway pressure (PAP)
for treatment. A split-night study is theoretically less sensitive than a full nocturnal
study because the AHI is assessed in half of the usual duration. A recent study, how-
ever, showed that the AHI derived from the first 2 or 3 h of a split-night study is of
sufficient diagnostic accuracy to rule-in OSA at an AHI threshold of five in patients
suspected of having OSA [56]. However, medical history is important in interpreta-
tion of the split-night study. For example, patient’s underlying unusual circadian
rhythm as well as sleep-onset/sleep-maintenance insomnia can alter the diagnostic
impression of the study. All things considered, the need to extend the “split-night”
study into a second nocturnal study is uncommon. Therefore, a “split-night” study not
only brings convenience to the patient by avoiding an extra evening of titration study
but also reduces the overall cost for the diagnosis and treatment of OSA. A split-night
study has become the “default” study type for individuals suspected of OSA.
64 C. Zhang et al.

Portable Monitoring (PM)

PM, or LCTs, is a simple methodology to diagnose OSA. PM testing gives limited

data (discussed in detail below) but perhaps is more comfortable for the subject and
thus offers a more natural perspective for the severity of OSA at home. However,
without a technician on site, the quality of PM studies is only as good as the tech-
nologies available.

Types of PMs (Type II–IV)

The American Academy of Sleep Medicine (AASM) has classified sleep studies
into four types, depending on the channels they record and evaluate [57]. Type I
PSG serves as a reference standard PSG, and it is usually a nocturnal, technician-
attended, full in-laboratory sleep study with 14–16 channel monitoring. Type II–IV
sleep studies are all simplified versions of Type I PSG [58, 59]. Type II records
essentially the same information as full in-lab PSG, except that technician attendance
is not present. SHHS, a large NIH-funded multiyear multicentered cohort study on
the cardiovascular and other consequences of sleep-disordered breathing, used Type
II portable monitors for diagnosis of OSA at home [60].
Type III PM has been the focus of an ongoing debate on the effectiveness and
utility of PMs in diagnosing OSA. Type III PM includes oximetry, at least two respi-
ratory channels (two airflow channels or one air flow plus one respiratory effort
channel) and ECG-monitored heart rate, but it does not include EEG, EMG, and
EOG. As a result, signals used to detect sleep stages and arousals from sleep (seen
in Type I and II sleep studies) are missing in Type III PM. Therefore, Type III PM
cannot calculate a true AHI, RDI, or sleep efficiency as it does not record the
denominator, sleep time. Instead, Type III PM can only report a value defined by
respiratory events divided by total recording time. However, the value reported
by Type III PMs does not necessarily imply sleep was recorded. Given that not all
study time is necessarily sleep time, reporting from Type III PM is a less sensitive
method than values from Type I or II PSG. Another major problem for Type III PM
is that without documenting sleep, an individual could wear the device (or give it to
someone else) and stay awake yielding an artifactually low AHI. It is worthwhile to
mention that “AHIs” or “RDIs” reported by different Type III PMs also vary with
different device manufacturers. Therefore, exact definitions of “AHI” or “RDI” vary
across different studies of Type III PMs.
The inability to detect respiratory event-related arousals (RERAs) may lead to
underestimation of the RDI and underrecognition of upper airway resistance
syndrome (UARS). Positional OSA can also be underdiagnosed by those Type III
PMs that do not include body position. Naturally, a “split-night” study is not appli-
cable for individuals who undergo Type III PM. A separate overnight in lab titration
study will likely be necessary for CPAP set up should the individual be diagnosed
of OSA by a Type III PM device.
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 65

Pulse oximetry and airflow are the physiological variables that are most commonly
measured in Type IV PM. As a result, the frequency of apneas or hypopneas (AHI) as
well as the baseline, mean, frequency, duration, and degree of oxyhemoglobin desatu-
ration can be estimated. Naturally, Type IV PMs share at least the same shortcomings
of Type III PM, and the current CMS requires a minimum of three channels to meet
the reimbursement criteria. However, we emphasize the sensitivity and specificity of
the various diagnostic techniques rather than the number of channels per se.

When Should PM Be Considered for Diagnosis of OSA?

While PM has an obvious advantage over PSG in its ease of use, the safety, reliability,
and diagnostic accuracy of PMs have been controversial [58]. Bodily injuries from
loose wires, faulty oximeter, and monitor disconnection by PMs have been reported.
Data loss in Type III and IV PMs have been estimated to be between 2 and 18%.
Additionally, interrater and intrarater reliability as well as night-to-night variability
of PM is greater than those of PSG. Currently, the scoring of apnea and hypopnea
events can be done either manually by a technologist or sleep physician, automatically
by the software of the PMs, or combined (manual correction on the automated scoring
is allowed). However, subtle points such as positional severity of OSA are more
difficult to characterize unattended PM than PSG. The lack of standardization of
testing and scoring protocols for PM is of greater concern as there are greater differ-
ences in signals recorded by different PM devices. In a comprehensive literature
review done by AASM, false negative results in unattended PM studies could be as
high as 15–17%. Likewise, false positive results in unattended home PM studies
could be as high as 30% [61].
The American Academy of Sleep Medicine published its first guidelines for
usage of PM in the diagnosis and management of patients with OSA in 2007 [57].
The guidelines stated the following principles for clinicians who consider PM as an
alternative to PSG. PM usage should only be considered as part of an integrative
patient evaluation for OSA, under the direction of a sleep specialist board certified
in sleep medicine.
The one-size-fit-all approach to screen for OSA in the general asymptomatic
population is not only medically and ethically unsound but also expensive and inac-
curate in terms of healthcare cost and clinical outcome. Whether an individual
should undergo PM vs. PSG depends on the individual’s OSA risk factors, physical
exam, medical comorbidities, suspicion of non-OSA sleep disorders, suspicion of
any secondary gain/loss from the test result, and an overall pretest probability for
OSA. PM should only be used for screening in subpopulations in which there is
substantial published knowledge on specificity and sensitivity of the test. PM can be
considered an alternative to PSG for patients with high pretest probability for mod-
erate to severe OSA. Furthermore, PM is not appropriate for diagnosis of OSA in
patients with major comorbid medical conditions that would lower the accuracy of
PM (i.e., severe pulmonary disease, neuromuscular disease, CHF, CSA). PM should
not be used for the diagnostic evaluation of OSA in patients suspected of having
66 C. Zhang et al.

Patient in Clinic

Low Risk Factors for OSA?

High chance for unreliable data?
Known co-morbid medical condition?
Suspicion of other co-morbiad sleep disorders?
No Yes

Portable Monitor PSG

Fig. 3.1 Portable monitor vs. in-lab PSG decision-making diagram

other sleep disorders such as CSA, periodic limb movement disorder (PLMD),
insomnia, parasomnias, circadian rhythm disorders, or narcolepsy. The utility and
efficacy of Type III PM have not been adequately studied for use in the occupational
setting in diagnosing at risk operators of motor vehicle operators, who, unlikely the
general population, often avoid an OSA diagnosis. Figure 3.1 illustrates the decision-
making diagram clinicians can use to decide if PSG or PM should be used to diagnose
OSA in a patient.
The United States CMS in 2008 approved reimbursement for the uses of PMs,
after Agency for Health Quality Research (AHQR) published a mostly positive
review of the PMs, particularly pertaining to its comparable clinical utility to predict
clinical outcomes (i.e., CPAP compliance rate) in a population with high pretest
probability [59, 62–64].

Current Roles of Autotitrating Positive Airway Pressure (APAP)

Autotitrating positive airway pressure (APAP) devices have been increasingly used for
titrating pressure and treating adult patients with OSA in the last decade [59, 65–68].
The devices can be used in place of in-lab continuous positive airway pressure (CPAP)
titration study when attended CPAP titration is not possible or patient comfort is a great
concern. They work by changing the treatment pressure based on patients’ airflow,
pressure fluctuations, or airway resistance.
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 67

As PMs are increasingly used as an initial diagnostic tool in populations with high
likelihood of moderate to severe OSA, APAP has been identified as a partner strategy
in the treatment phase to replace the more costly CPAP titration with in-lab PSG.
We note here that the 2008 AASM Guidelines for APAP stated that APAP devices
can only be used for unattended treatment of patients with moderate and severe OSA
without significant comorbidities such as CHF, COPD, and CSA [61]. Since then, a
large VA study by Berry et al. demonstrated that diagnoses by PM followed by APAP
titration resulted in comparable CPAP adherence and clinical outcomes to using
traditional in-lab PSG [69]. However, as APAP technology is fast evolving, different
APAP devices differ not only in their sensitivities to detect severity of disordered
breathing but also in their responses to disordered breathing. Therefore, overall
assessment of cost-effectiveness of APAP combining with PMs is complicated.

Cost Effectiveness of PSG vs. PM

Although the cost of PM devices has seen a substantial drop in recent years, the total
health care cost of evaluating and treating individuals with OSA using PM com-
pared to PSG has not been studied adequately and largely controversial. Though
gross cost savings were frequently reported, the high false negative rate of PMs
along with the current guideline that all negative tests of PMs should be referred to
a full in-lab PSG by a sleep specialist translates into high cost if the currently avail-
able PMs were to become the mainstream of screening tools. Furthermore, few cost
analyses compared usage of PMs to increasingly popular use of split-night study
protocols, in which both diagnostic PSG and titration studies are done in a single
night. Further studies using a decision model are much needed to provide a theoretical
framework as well as evidence to ascertain the pretest disease probability above
which portable studies would be economically attractive as an initial test in the
assessment of suspected OSA [70].

Utilities of Multiple Sleep Latency Test (MSLT) in OSA

MSLT is one of a few currently available de facto standard tests to measure physi-
ological sleep tendency in the absence of external alerting factors. The test is based
on the premise that the degree of sleepiness is correlated with and therefore reflected
by sleep latency (the amount of time it takes for the individual to fall asleep) [71].
MSLT is usually ordered to diagnosis narcolepsy or other conditions of hypersomnia.
The individuals with these conditions typically have reduced sleep-onset latency
and early onset of REM sleep [71]. However, MSLT is occasionally indicated to
quantify objectively sleepiness, e.g., residual daytime sleepiness despite presumed
adequate CPAP treatment of OSA. For example, professional drivers or pilots with
OSA may at times be subjected to medicolegal actions in order to objectify whether
their residual sleepiness is significant enough to keep them off the roads. The test is
usually done immediately following an overnight in-lab PSG in order to control for
68 C. Zhang et al.

the patient’s sleep characteristics. The test asks the patient to have four or five naps
(2 h between each) in a naturally dim-light environment during the day. The sleep
onset latency is recorded for each nap. If the patient does not fall asleep within
20 min of each nap, the sleep onset latency is assumed to be 20 min. The average of
the sleep onset latency is used as objective measure of sleepiness. With high test–
retest reliability and inter-rater/intra-rater reliabilities, MSLT has demonstrated its
ability to differentiate normal healthy subjects from those with pathologic sleepi-
ness on both driving simulators as well as long-term road accidents [72, 73].
However, MSLT is not a reliable predictor of traffic accidents, emphasizing the need
for more research in this area.

Future Outlook

One of the ongoing research goals in OSA is to identify a relatively easily assayed
biomarker. For example, recent studies have shown that amylase in saliva (i.e.,
salivary amylase activity as well as amylase mRNA levels) are elevated in individuals
with EDS and OSA [74]. Among individuals with OSA, who are assumed to have
higher sleep drive, systemic inflammation maybe involved in the pathogenesis of
OSA [75]. Studies using microarrays looking at gene expression have shown that
overnight expression of oxidative stress response genes such as antioxidant enzyme
superoxidase dismutase 2 (SOD2) and catalase are up-regulated [76]. Proteomic
analyses of serum and urine may yield future technique for identifying individuals
with OSA. Even though there is a lack of data in adult population, recent findings
suggest that proteins such as gamma-carboxyglutamic acid, perlecan, and gelsolin
are differentially expressed among children with OSA and the control. Specific
subpopulations of leukocytes such as TNF-alpha, IL-6, and some T lymphocytes
have been found to be elevated among patients with OSA [77, 78]. Brief paroxysmal
bursts of alpha activity have been identified before serious driving errors in simulation
studies [79]. Similarly, a significant increase of eye blinks, in both number and duration,
have been described before driving errors. Furthermore, an alteration of eyes blinking
duration has been observed with increased driving time. With identification of more
reliable biomarkers, the tasks of diagnosing OSA and sleepiness individuals will
become less challenging.

Summary Outline

• In clinic pretest screening questions (symptoms of snoring, daytime sleepiness,

and common comorbidities) for OSA are important to efficaciously diagnose
OSA. In some special clinical scenarios (i.e., occupational clinic), screening for
OSA should rely more on objective anthropometric measurements.
• OSA risk factors include obesity, older age, male gender, postmenopausal status,
Asian/African American races, tobacco, and alcohol use.
3 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 69

• The diagnostic criteria of sleep apnea are not uniform, but most of them try to
characterize the frequency of sleep-disordered breathing events along with the
degree of oxygen desaturation of each event.
• Three most commonly used diagnostic criteria for OSA are the AASM
“Recommended” Criteria (or the “Medicare” Criteria), AASM “Alternative”
Criteria, and “the Chicago” Criteria.
• There are four types of sleep studies available. Both in-lab PSG, or Type I, and
portable monitors (PM), or Type II–IV, are being used for diagnosis of OSA.
PSG is the gold standard test for diagnosis of OSA. PM offer a less-expensive
and in-home alternative, with limitations in both sensitivity and specificity.
• A “split-night” study not only brings convenience to the patient by avoiding an
extra evening of titration study but also reduces the overall cost for the diagnosis
and treatment of OSA. A split-night study has become the “default” study type
for individuals suspected of OSA.
• Whether an individual should undergo PM vs. PSG depends on the individual’s
OSA risk factors, physical exam, medical comorbidities, suspicion of non-OSA
sleep disorders, suspicion of any secondary gain/loss from the test result, and an
overall pretest probability for OSA.

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Chapter 4
Approach to Hypersomnia

James A. Rowley

Introduction

Hypersomnia or excessive daytime sleepiness is a major health problem in the

United States, with several general surveys indicating that approximately one-third
of Americans report daytime sleepiness at least a few days per month with approxi-
mately 6–8% reporting daily symptoms [1, 2]. Daytime sleepiness results in problems
with vigilance, cognitive function, memory, concentration, and mood, generally
leading to deterioration in school and/or job performance and productivity, social
relationships and most importantly, driving skills. Driving drowsy is an increasingly
prevalent problem. In the 2005 National Sleep Foundation survey, 60% of Americans
reported driving a car while drowsy in the last year [3] while the 2009 poll found
that 23% admitted driving drowsy at least once per month [4]. It has been estimated
that up to 10–15% of accidents may be related to sleepiness or fatigue [5] with
increasing severity of sleepiness associated with increased risk of an accident [6].
Therefore, an understanding of the causes and differential diagnosis of daytime
sleepiness is important. This chapter will discuss the determinants of sleepiness, the
commonly used methods of measuring sleepiness, the differential diagnosis and a
practical approach to the diagnosis of sleepiness, with emphasis on which patients
need referrals to a sleep center.
Before this discussion it would be helpful to first define abnormal daytime sleep-
iness. Secondary to circadian rhythms, sleepiness in the mid-afternoon is a normal
phenomenon (see Determinants section below). Therefore, sleepiness at other times
of the day or in situations in which alertness is warranted (meetings, lectures, driving)

J.A. Rowley (*)

Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine,
Wayne State University School of Medicine, Harper University Hospital, Detroit, MI, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 73
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_4,
© Springer Science+Business Media, LLC 2012
74 J.A. Rowley

is generally considered abnormal. Another important concept is difference between

physiologic and manifest sleep tendency. Physiological sleep tendency is the tendency
to fall asleep in the absence of alerting factors and is determined by the factors discussed
in the next section. In other words, sleepiness is also a physiologic state, similar to
hunger or thirst [7, 8]. As such, the subjective feeling of sleepiness can be reduced
by motivation, excitement, exercise, and other competing needs. Thus, manifest
sleep tendency varies from moment to moment and is influenced by factors such as
light, noise, and motivation. Reducing impinging stimuli or soporific conditions
(such as reading or watching TV) serves to unmask the physiologic sleep tendency,
not cause it. In other words, a truly alert individual would not be sleepy in a low
stimulus environment.

Determinants of Daytime Sleepiness

Sleep Factors

Quantity of Sleep

An individual’s optimal sleep time is that time that allows him/her to maintain alert-
ness throughout the day. For most individuals, this time is between 7 and 8 h each
night. Even one night of sleep deprivation, generally to 4 h of sleep or less, can lead
to increased sleepiness the following day [9]; this is a situation most individuals have
experienced. More common, however, is chronic sleep deprivation, generally to less
than 6 h per night over consecutive nights. Based upon two surveys, approximately
15–20% of Americans sleep less than 6 h per night on a regular basis; in addition,
20–30% of Americans reporting getting less than their required hours of sleep to feel
refreshed and alert during the day [3, 4]. In analyses of the determinants of daytime
sleepiness in two large cohorts, decreasing subjective total sleep time was associated
with increased likelihood of subjective [1] or objective daytime sleepiness [10].

Quality of Sleep

The quality and continuity of sleep are important determinants of sleep. Sleep dis-
orders that are characterized by brief arousals, such as the obstructive sleep apnea
hypopnea syndrome (OSAHS), are examples of disorders that effect the quality of
sleep and are associated with daytime sleepiness [11, 12]. However, other medical
conditions, such as asthma, gastroesophageal reflux disease, and various pain syn-
dromes, can also disrupt the continuity of sleep and possibly contribute to daytime
sleepiness in these patient populations.
It should be noted, however, that studies do not universally indicate that there is a
clear correlation between the degree of sleep discontinuity in OSAHS and the degree
4 Approach to Hypersomnia 75

Table 4.1 Medication Antihistamines

classes frequently associated
Benzodiazepines
with daytime sleepiness
Antidepressants
Narcotics
Alcohol
Barbiturates

of daytime sleepiness. For instance, in population studies, the prevalence of daytime

sleepiness in subjects with OSAHS is low, ranging from 16 to 22% [13–16]. In the
Pennsylvania cohort analysis, the apnea–hypopnea index was not found to be inde-
pendent predictor of subjective excessive daytime sleepiness [1]. Finally, correction
of the AHI by continuous positive airway pressure (CPAP) does not result in improve-
ment in excessive daytime sleepiness in a large proportion of patients [17, 18].

Circadian Rhythm

A biphasic pattern of sleep tendency is observed when adults are testing for physiologic
sleepiness by asking them to sleep at 2-h intervals in a low-stimulus environment,
such as a darkened room [19]. As expected, the shortest latencies to sleep were
observed during the early morning hours, 2–6 am. However, there was also shorter
sleep latencies observed in the mid-afternoon, between 2 and 6 pm, corresponding
to the time of day that many individuals will report an increased feeling of sleepiness
and the time of the “siesta” prevalent in many cultures.

Medications

Several classes of medications can contribute to daytime sleepiness (see Table 4.1).
The antihistamines, particularly those bought over the counter (such as diphenhy-
dramine), are amongst the most common causes of sedation yet are often not thought
of as drugs by patients and therefore not listed as medications when asked. Of the
newer antihistamines, only cetirizine, which crosses the blood–brain barrier, is
associated with daytime sleepiness.
Many psychoactive medications cause daytime sleepiness. While the benzodiaz-
epine sedative hypnotics are generally taken at bedtime to help induce sleep, several
of these agents are intermediate or long acting (temazepam and estazolam), and
therefore can cause residual sleepiness during the day even when taken at bedtime.
In addition, the anxiolytic benzodiazepines (diazepam, alprazolam) can cause sleep-
iness in some individuals. Several antidepressants, such as amitriptyline, trazodone,
and paroxetine, have been associated with daytime sleepiness, as have barbiturates
such as phenobarbital. Other drugs that have been associated with sleepiness include
narcotic agents and alcohol.
76 J.A. Rowley

Demographic Factors

Age

Population studies have indicated that young age is associated with increased daytime
sleepiness [1, 20]. In particular, in a large population study from Pennsylvania,
using a subjective question regarding daytime sleepiness, found that young age
(<30 years) and extreme older age (>75–80 years) are associated with an increased
propensity to excessive daytime sleepiness [1]. The reasons underlying this finding
are unclear, though the authors speculate that the increased propensity in the young
is secondary to unmet sleep needs while in the extreme elderly it is related to increasing
medical problems. Studies utilizing objective measures of sleepiness, such as the
multiple sleep latency test (MSLT), have also shown that younger age is associated
with increased propensity to daytime sleep [21, 22].

Gender

Several studies [23, 24], though not all [1, 2], have shown that men have a higher
propensity to sleepiness using subjective measures of sleepiness, such as the Epworth
Sleepiness Scale (ESS). In addition, one study using the MSLT also showed that men
had a higher propensity to sleep than women [10]. Reasons underlying this difference
have not been systematically investigated, though the authors of at least one study
using the Epworth hypothesized that women and men answer the questions differently
and that the Epworth is more sensitive to sleepiness in men than woman [24].

Race

Several large population and clinical cohorts have found that African-Americans
have higher propensity to excessive daytime sleepiness as measured by the ESS
[23, 25–27]. Authors of these studies have hypothesized that the higher Epworth in
African-Americans could be due to shorter total sleep time [28] or an increased
prevalence of sleep-disordered breathing in African-Americans [29]. In one of the
studies, the authors found that the increased Epworth score in African-Americans
was secondary to higher scores on just two of the items (#6 and #7, see Table 4.2);
these data suggest there may be sociocultural differences that cause of the wording
of the question to be interpreted differently by different groups. It should be noted
that there have been no studies using objective measures of sleepiness to confirm the
observed racial differences in the Epworth scale.

Obesity

Several studies using subjective measures of sleepiness, including cohort [30, 31] and
population studies [1], have indicated that obese patients are excessively sleepy
4 Approach to Hypersomnia 77

Table 4.2 Situations in the Epworth sleepiness scale

Sitting and reading
Watching TV
Sitting inactive in a public place (e.g., a theater or a meeting)
As a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking to someone
Sitting quietly after a lunch without alcohol
In a car, while stopped for a few minutes in traffic

independent of the presence of sleep-disordered breathing. Studies using objective

measures of sleepiness have confirmed these findings, generally showing that the
increased propensity for daytime sleepiness occurs when the body mass index is
>28–30 kg/m2 [10, 32]. Vgontzas and colleagues have proposed that obesity is
related to sleepiness independent of OSAS because an interaction between increased
cytokine release (particularly IL-6 and TNF-a) and relative hypoactivity of the
hypothalamic-pituitary axis, both of which are observed in obesity [33, 34]. There is
also evidence that diabetes is independently associated with daytime sleepiness [1, 35];
therefore, insulin resistance may represent an additional mechanism that explains
the association between obesity and sleepiness.

Pathology of the Central Nervous System

A normally functioning nervous system, particularly in the areas that control the wake-
fulness-sleep cycle is critical. Narcolepsy is the best example as it has been shown that
the destruction of hypocretin-secreting neurons in the posterior hypothalamus, which
is now understood to be the primary pathologic finding in narcolepsy [36].

Measurement of Daytime Sleepiness

Multiple Sleep Latency Test (MSLT)

The MSLT measures the physiologic sleep tendency by measuring the latency to
sleep in the absence of alerting factors such as noise and light [7, 22]. During the
test, which is generally performed the day after a full night sleep study, the patient
is instructed to fall asleep in bed, in a dark, quiet room at 2-h intervals 5 times during
the day beginning 1.5–2 h after awakening. Naps are terminated either at 20 min if
there is no sleep or 15 min after the onset of sleep. The latency to sleep for each nap
is defined as the time from the start of the test to the first 30-s epoch of any stage of
sleep. The individual latencies are then averaged determining the mean daytime
78 J.A. Rowley

sleep latency. Generally, mean latencies greater than 15 min are considered normal;
a sleep latency £5 min is considered severe or pathologic. In addition, there should
be no rapid-eye movement (REM) sleep during any of the nap opportunities. The reader
is referred to the American Academy of Sleep Medicine practice parameter for
complete guidelines for the optimal performance of the MSLT [37].
The MSLT has been shown to be a valid and reliable test of daytime sleepiness
[22, 38]. It correlates with reported total sleep time [10] and it can detect changes in
sleepiness secondary to acute changes in sleep time [7], and drugs such as caffeine
and alcohol [39–41]. It also appears to be sensitive to the treatment of sleep disorders
such as obstructive sleep apnea [17, 42] and narcolepsy [43], though this is not a
universal finding [17, 44].
The MSLT is considered essential in the evaluation of patients with suspected
narcolepsy. Patients with narcolepsy generally have pathologic sleep latencies
(<5 min) and have a sleep onset REM period (SOREMP) on at least two of the five
naps. Summary analysis shows that the presence of two or more SOREMPs on a
MSLT has a sensitivity of 0.78 and a specificity of 0.93 for the diagnosis of
narcoelspy [22]. Thus, in the absence of cataplexy, the presence of two or more
SOREMPS is considered diagnostic of narcolepsy. It should be noted that two or
more SOREMPS have been noted in up to 13% of the general population [45] and
in approximately 5% of patients with OSA [46]. Thus, the presence of SOREMPS
on a MSLT should be considered within the overall clinical context of each
individual patient.
The primary disadvantage of the MSLT is lack of discrimination between normal
and sleepy populations because of a wide range of normal values. In an analysis of
published studies performing the MSLT in normal populations, the authors found that
the mean latency for the five-nap MSLT for normal subjects 11.6 ± 5.2 min [22]. Using
a two-standard deviation to determine a normal range, the normal range for controls
would be 1–20 min, which is clearly not discriminatory. Another disadvantage of the
MSLT is that it is laboratory based, requiring trained sleep personnel to perform.
Based upon the strengths and limitations above, the American Academy of Sleep
Medicine has identified indications for performing the MSLT [37]. Indications that
were recommended as a standard of care (highest level of care) were: (1) the use of
the MSLT as part of the evaluation of patient with suspected narcolepsy to confirm the
diagnosis; and (2) repeat MSLT is indicated if suspected narcolepsy but first test was
inadequate or did not provide confirmation of the diagnosis. The committee felt that the
MSLT may be indicated in the evaluation of a patient with suspected idiopathic hyper-
somnia to differentiate from narcolepsy. Finally, the MSLT is not routinely indicated in
the evaluation or management of OSA, insomnia, or circadia rhythm disorders.

Maintenance of Wakefulness Test (MWT)

While the MSLT is a test of physiologic sleepiness, the maintenance of wakefulness test
(MWT) is a test of manifest sleepiness as it tests the ability of the patient to stay awake
4 Approach to Hypersomnia 79

in a low stimulus environment. The MWT is felt to be more clinically relevant as it more
closely reflects the challenge patients face in soporific situations of everyday life.
The MWT protocol is similar to that of the MSLT (4 naps, spaced 2 h apart) except that
the patient is instructed to stay awake while sitting upright in a low-stimulus environ-
ment (light level up to 0.13lux [equivalent of 7.5 W light bulb]). In the MWT, indivi-
dual tests are terminated at 40 min if no sleep occurred or there is three consecutive
epochs of stage N1 sleep or any epoch of any other stage of sleep. Similar to the MSLT,
sleep is defined as the time from the beginning of the test until the first epoch of any stage
of sleep. Latencies from the four naps are then averaged to give a mean onset latency.
Mean latencies for the MWT have been shown to be longer than mean latencies for
the MLST for both normal subjects [22] and patients with sleep apnea [44, 47] and
narcolepsy [48] confirming that the MWT is measuring a different aspect of sleepi-
ness than the MSLT. However, the degree of correlation between the MSLT and MWT,
while significant, is small [48, 49]. The MWT is sensitive to treatment effects, having
been shown to improve with the treatment of OSA with CPAP [47, 50] and with
modafinil for narcolepsy [51]. One older study indicated that the MWT may be more
sensitive for treatment effects in sleep apnea as there was a significant increase in the
mean latency for the MWT but not for the MSLT with CPAP [44].
The MWT has been proposed as a clinical test to determine if a subject can safely
operate a car, truck, or airplane. The limited number of studies on the predictive role of
the MWT for driving safety have found that a shorter sleep latency on the MWT corre-
lates with decreased performance on a driving simulator [52, 53]. However, the evidence
for the predictive ability of the MWT for real-world driving is less clear [47, 54], and
there is evidence that performance on a driving simulator performance does not correlate
with real-world driving [55], limiting the value of the MWT for predicting driving safety.
Nonetheless, the Federal Aviation Administration requires the MWT for pilots with
sleep disorders to certify that they are safe to fly commercial airplanes [56].
Similar to the MSLT, a disadvantage of the MWT is a wide range of normative
values. In an analysis of published studies performing the MWT in normal popula-
tions, the authors found that the mean latency for the MWT is 30.4 ± 11.2 min [22].
Thus, the cutoff value of a normal study is not clear, limiting applicability, particularly
for the evaluation of workplace safety. Also, there is evidence that the MWT is
susceptible to changes in motivation [57, 58].
Based upon the strengths and limitations above, the American Academy of Sleep
Medicine has identified indications for performing the MWT [37]. The MWT may
be indicated to assess an individual’s ability to remain awake when his/her ability to
remain awake constitutes a public or personal safety issue or to assess the effect of
treatment in individuals with excessive daytime sleepiness.

Epworth Sleepiness Scale (ESS)

The ESS was developed as an easy to use scale to objectively measure daytime sleep-
iness without the requirement for in-laboratory testing [8, 59, 60]. The ESS was
80 J.A. Rowley

designed to measure the general level of excessive daytime sleepiness or sleep

propensity in adults. As developed, it was intended to measure daytime sleepiness
that persists over periods of more than 1 week, independent of changes in time of day
and from day to day. In addition, it was designed to overcome the fact that different
individuals will have different routines, some that facilitate and others that inhibit
sleep. In addition, it asks for the likelihood of falling asleep in different situation.
It does not ask how often someone falls asleep in a certain situation as the answer
would depend on how often the individual finds him/herself in that situation.
In answering the ESS, the patient rates his/her likelihood of dozing off in eight
situations (Table 4.2) which range from highly soporific (watching TV or reading)
to those requiring attention (talking to someone, sitting in a meeting). Each situation
is scored on a scale of 0, will not doze off, to 3, high likelihood of dozing off; the
scores from each situation are added, giving a final score between 0 and 24.
Traditionally, a score of 10 or above has been used to distinguish between individuals
with and without daytime sleepiness, though evidence from one study suggested
that a cutoff of 12 may more reliably indicate an increased tendency to fall asleep
on the MSLT [10]. Most studies have suggested that the ESS has good test–retest
reliability [60–62] though one group found that while the mean ESS was similar
over time there was actually a large degree of variation between individuals [63].
Studies have shown that the ESS correlates with different sleep disorders [64] and
has been found to correlate with severity of OSAHS [8, 12].
There are several limitations to the ESS [65]. The major limitation of the ESS is
that it does not correlate well with the MSLT. In other words, while a higher ESS score
indicates a greater propensity to fall asleep on the MSLT [10], a higher score does
not necessarily predict a shorter sleep latency on the MSLT [66, 67]. For instance,
in a group of 102 patients evaluated for excessive daytime sleepiness, primarily
patients with sleep-disordered breathing, 68% of patients with a normal sleep
latency on the MSLT had an ESS score ³10 while 36% of patients with a sleep latency
<5 min on the MSLT had a ESS <10. Therefore, on initial evaluation, the ESS may
or may not indicate that the patient is truly sleepy as measured objectively by
the MSLT. In addition, the ESS also does not ask about other situations in which the
propensity for sleep may be important (such as work) nor does it include questions
about naps. The noninclusion of naps is important as many sleep physicians have
found that some patients will have low ESS scores but report multiple naps per day.
Contextual factors are another potential limitation. In a study of 146 subjects, the
answer to individual items on the ESS was shown to be influenced by contextual
factors such as position (lying down v. sitting up), location (public v. private), and
interest level (interesting v. boring) [68]. For instance, a patient lying in bed watch-
ing TV was more likely to rate a higher propensity to falling asleep than a patient
watching TV sitting up. While these contextual elements are not present in the ESS
as presented to patients, these results suggest that different individual patients may
interpret the situations in different contexts, which could alter scores. Finally, the
ESS was developed and has been primarily validated in white populations. While it
has been validated in other populations and non-English cultures [61, 62], it is
unclear if the ESS measures sleepiness consistently between groups or if different
4 Approach to Hypersomnia 81

groups could interpret individual items differently. For instance, differing interpretation
of items #6 and 7 on the ESS was found in a study comparing the ESS between
whites and African-American populations [25]. In addition, there is evidence that
men and women will answer the Epworth differently; in the Sleep Heart Health
Study, men and women equally reported daytime sleepiness when asked as a simple
yes/no question but women had an overall lower Epworth than men [24].
While the ESS may not provide an accurate indication of which individuals are
sleepy, there are several studies that show that higher ESS scores decrease with
effective treatment of the primary sleep disorder, including OSAHS and narcolepsy
[17, 51, 69]. In other words, the ESS can provide valuable information to the physician
in determining whether the treatment plan has been effective for the patient and it is
widely used for this purpose.

Summary of Measurements of Excessive Daytime Sleepiness

In summary, there are three standard measurements of excessive daytime sleepiness,

the MSLT, MWT, and ESS. All three tests have advantages and limitations for their
use in the evaluation of excessive daytime sleepiness, including evaluation of work-
place safety. The evidence suggests that these tests likely measure different aspects
of sleepiness, do not correlate well with each other [48, 49, 66, 70], and respond
differently to treatment [17]. Thus, no test should be considered “gold standard” [70]
and the individual test chosen to evaluate sleepiness in any individual patient should
be chosen based upon the needs of the evaluation (for instance, a MSLT if narcolepsy
suspected; a MWT for an airline pilot seeking certification to fly).

Differential Diagnosis

The differential diagnosis of excessive daytime sleepiness is presented in Table 4.3.

Key symptoms and characteristics of each are briefly presented in this section.
Chronic insufficient sleep is probably the most common of these diagnoses given
the prevalence of sleep deprivation in adults [3, 4], but is an infrequently made diag-
nosis because chronic sleep deprivation is not looked upon as a medical problem.
The two major characteristics of chronic insufficient sleep are habitual sleep epi-
sodes that are shorter in duration than expected for age (generally 7–8 h for adults)
and longer than normal sleep episodes on weekends or vacations. Other clues to
diagnosis include patient’s work schedule, number of jobs, family and other social
obligations, and hours of television and internet use. Chronic insufficient sleep is a
clinical diagnosis based upon the patient’s sleep and social history. However, many
patients with other sleep disorders also have insufficient sleep. Therefore, it is
important to consider other causes before considering chronic insufficient sleep the
primary reason for a patient’s daytime sleepiness. In addition, in patients with other
82 J.A. Rowley

Table 4.3 Differential diagnosis of daytime sleepiness

Behaviorally induced insufficient sleep syndrome
Obstructive sleep apnea
Narcolepsy
Restless leg syndrome/periodic limb movement disorder
Disorders of the sleep–wake cycle
Sleep phase delay syndrome
Shift work
Idiopathic hypersomnia
Drug effect

disorders who report continued daytime sleepiness despite ongoing primary therapy
for that disorder, should be evaluated for the presence of chronic insufficient sleep.
OSAHS is characterized by recurrent collapse of the upper airway during sleep;
the episodes of collapse are associated with oxyhemoglobin desaturation and recurrent
arousals [71, 72]. Patients generally present with the complaint of loud snoring that
is bothersome to the bed partner, witnessed apneas, nocturnal, gasping and choking,
morning headaches, and nonrefreshing sleep. OSAHS is diagnosed by polysom-
nography; therefore, referral to a sleep center for diagnostic testing is generally
recommended.
Narcolepsy is a chronic neurologic condition characterized by both excessive
daytime sleepiness and impaired regulation of REM sleep [73, 74]. Pathologically,
narcolepsy is associated with destruction of hypocretin-producing neurons in the
hypothalamus and decreased hypocretin in the cerebrospinal fluid [36, 75, 76].
Narcolepsy is also tightly associated with the human leukocyte antigen DQB1*0602
[77]. In addition to the daytime sleepiness, narcoleptic patients often have cataplexy,
hypnagogic hallucinations, and sleep paralysis. Cataplexy, considered pathogno-
monic of this disorder, is sudden muscle weakness brought on by intense emotion
such as laughter or anger. The muscle weakness can affect any muscle group and
manifest as falling, facial or head droop, or dropping objects. Hypnagogic halluci-
nations, intense dream-like hallucinations, at the beginning of the night soon after
the patient falls asleep, and sleep paralysis, profound weakness of the skeletal
muscles generally occurring during awakenings during the night, are not specific to
narcolepsy; both have been reported by patients with severe obstructive sleep apnea,
and idiopathic hypersomnia while sleep paralysis can also occur as a sporadic para-
somnia. Because both a nocturnal sleep study and a MSLT are required for the
diagnosis of narcolepsy, referral to a sleep center is recommended.
The restless leg syndrome (RLS) is a characterized by a (1) feeling of motor
restlessness or urge to move the legs; (2) relief with leg movement; (3) restlessness
occurs primarily while legs are relaxed (sitting with legs reclined or lying down);
(4) restlessness occurs primarily in the evening [78, 79]. RLS is often associated
with recurrent leg kicking during sleep, the main characteristic feature of periodic
limb movement disorder (PLMD). RLS often presents as insomnia because the rest-
lessness prevents the patient from falling asleep; however, if there are prominent leg
4 Approach to Hypersomnia 83

movements, daytime sleepiness can be the presenting symptom. RLS is a clinical

diagnosis, requiring only the presence of the four major symptoms noted and is
generally treated with dopaminergic agents.
In general, disorders of the sleep–wake cycle are characterized by a misalignment
between the patient’s sleep cycle and the society norm (which is generally a bedtime
between 10 pm and midnight with awakening between 6 and 8 am) [80, 81]. Most
shift workers, particularly those with night shifts or frequently rotating shifts, will
complain of excessive daytime sleepiness because it is difficult to achieve normal
sleep when the major sleep episode begins in the morning. Patients with sleep phase
delay syndrome tend to go to bed after midnight (bedtime is delayed relative to
societal norm) and if allowed, will generally sleep uninterrupted for 7–8 h, awakening
refreshed. The shifted sleep pattern becomes abnormal when the patient must
awaken earlier than his/her usual time, generally because of employment; the short-
ened sleep time leads to insufficient sleep and excessive sleepiness.
Idiopathic hypersomnia is characterized by constant daytime sleepiness and
frequent daytime sleep episodes lasting 1 h or more that are generally not refreshing
[82–84]. The MSLT demonstrates moderate to severe shortening of the daytime
sleep latency (<10 min) but there is generally no REM sleep during any of the naps.
Idiopathic hypersomnia is a difficult diagnosis to make as symptoms and findings
overlap with other disorders, particularly narcolepsy. It is generally diagnosed only
after patients have had a full sleep evaluation, including a sleep log, polysomnography,
and a MSLT, and other causes of daytime sleepiness, particularly chronic insufficient
sleep, OSAHS, narcolepsy, and RLS, have been ruled out.

Approach to the Sleepy Patient

A systematic approach to the patient presenting with excessive daytime sleepiness

is important to both recognizing and managing these patients. Patients identified as
possibly having obstructive sleep apnea or narcolepsy should be referred to a sleep
center for optimal diagnosis and treatment. Other patients, particularly those on
medications associated with sedation or not getting sufficient sleep, can be counseled
and managed by the primary care physician.
Identification of these patients begins with asking every patient if they are exces-
sively sleepy during the day. If the answer is “yes,” there are six simple follow-up
questions to be asked (outlined in Fig. 4.1).
1. Do you snore? If the answer is yes and the snoring is loud, habitual, and bother-
some, obstructive sleep apnea is likely. Referral to a sleep laboratory for a sleep
study is recommended in all of these patients.
2. Do your legs feel restless when you relax or do your legs kick at night? If the
answer is yes, RLS should be considered. A trial of a dopamine agonist such as
ropironole or pramipexole is recommended with referral to a sleep specialist if
not successful.
84 J.A. Rowley

Fig. 4.1 Approach to the patient with daytime sleepiness

3. Do you have weakness in your muscles with sudden or strong emotion such as
laughter? This question attempts to identify cataplexy, the pathognomonic
symptom of narcolepsy. If the patient has cataplexy or any of the other major
symptoms of narcolepsy (automatic behaviors, sleep paralysis, or hypnagogic
hallucinations), referral to a sleep center for a sleep study and MSLT is
recommended.
4. What is your sleep schedule? If the patient’s sleep schedule is outside the societal
norm (to bed 10 pm to midnight, out of bed 6–8 am), or the patient works shifts,
a sleep–wake cycle disorder must be considered. Referral to a sleep center is
recommended.
5. What medications do you take? The physician should obtain a complete medica-
tion list, including common over-the-counter agents. If the patient is taking a
medication associated with daytime sleepiness (Table 4.1), the physician should
make a therapeutic substitution if possible.
6. Do you sleep much longer on weekends or on a vacation? Most individuals who
are sleep deprived attempt to make up for the lost sleep by “sleeping in” on
weekends or during vacations. These individuals will often report less sleepiness
after obtaining the additional sleep. Individuals who are chronically sleep
deprived should be counseled regarding the importance of regular sleep and of
obtaining at least 7–8 h of sleep per night.
4 Approach to Hypersomnia 85

In summary, individuals with symptoms consistent with one of the major sleep
disorders, such as obstructive sleep apnea or narcolepsy should be referred to a
sleep center for diagnosis and management. Individuals with symptoms consistent
with drug effect or chronic insufficient sleep can be initially counseled by their
primary physician. If a medication change or additional sleep does not result in
improvement in the daytime sleepiness, referral to a sleep center is recommended.

Summary of Keypoints

• Hypersomia is defined as sleepiness during times of the day or during situations

in which alertness is warranted.
• Sleep factors that influence hypersomnia include quantity of sleep, quality of
sleep, and circadian rhythms.
• Medications associated with hypersomnia include benzodiazepines, antihistamines,
many antidepressants and antipsychotics and narcotics.
• Demographic factors that are clearly associated with hypersomnia are younger
age and obesity. Males and African-Americans may also be predisposed to
increased daytime sleepiness.
• The MSLT is an objective measure of physiologic sleep propensity. While the
MSLT is generally reliable and valid, it has poor discriminatory value and is
primarily used to diagnose narcolepsy.
• The MWT is an objective measure of manifest sleep propensity. The MWT is
primarily used to determine if patients in high risk jobs (such as truck drivers or
pilots) can remain awake for sustained periods.
• The ESS is a subjective measurement of sleep propensity. While considered a
valid and reliable test, it does not correlate with the MSLT and is best used to
measure response to therapy.
• Differential diagnosis of hypersomnia includes insufficient sleep, sleep-disordered
breathing, narcolepsy, RLS, shift work, delayed sleep phase syndrome, and
medication effect.

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Chapter 5
Obstructive Sleep Apnea: Epidemiology
of Sleep Apnea

Jessie P. Bakker, Atul Malhotra, and Sanjay R. Patel

Keywords Sleep apnea, obstructive • Polysomnography • Epidemiology •

Prevalence • Risk factors • Disease progression • Lung

Introduction

The most common sleep disorders in the clinic are those falling into the category of
sleep-disordered breathing, which comprises a group of conditions characterized by
intermittent cessations (apneas) or reductions (hypopneas) in respiration during
sleep. These events can result from either the absence of ventilatory drive (central
sleep apnea), or a physical blockage occurring in the upper airway during which
there are still attempts to breathe (obstructive sleep apnea; OSA). In the laboratory,
central and obstructive apneas can be easily distinguished as the former are accom-
panied by an absence of respiratory effort, whereas the latter are accompanied by
ongoing (often out-of-phase) thoracic and abdominal movements. Although it is
more straightforward to think of central sleep apnea and OSA as separate diseases
with discrete etiologies, many patients exhibit both types of events hence there are
likely to be shared pathophysiologic mechanisms.

J.P. Bakker
Department of Medicine, University of Otago, Wellington, New Zealand
A. Malhotra
Sleep Disorders Program, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
S.R. Patel (*)
Division of Sleep Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 91
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_5,
© Springer Science+Business Media, LLC 2012
92 J.P. Bakker et al.

The spectrum of obstructive sleep-disordered breathing has historically been

described as ranging from simple snoring, through upper airway resistance syndrome
(UARS), to full-blown OSA. While the idea of a spectrum has its merits, it suggests
that simple snoring is benign, which recent evidence indicates may not be the case [1].
This concept also implies that over time an individual progresses from being normal
to developing simple snoring then UARS and then finally OSA. Thus far, there are
insufficient longitudinal data to confirm or refute this supposition. UARS is most
often defined as the presence of frequent respiratory effort-related arousals (RERAs),
arousals from sleep due to increased work of breathing secondary to increased airway
resistance where the reduction in airflow is insufficient to meet criteria for hypopnea.
Whether UARS is a clinical entity separate from, or simply a milder form of, clini-
cally defined OSA is debatable. Laboratories which use relatively strict criteria for
defining hypopnea (i.e., based on 4% O2 desaturation) frequently score RERAs,
whereas laboratories using more liberal criteria (i.e., discernable decrement in flow
with either desaturation or arousal) essentially never observe RERAs.
The repeated occurrence of obstructive apneas and hypopneas overnight leads to
a predictable pattern of events: a reduction of inspiratory airflow leading to episodic
hypoxemia and hypercarbia, an increase in respiratory effort, arousals in order to
restore normal respiration, fragmented sleep, and in many cases excessive daytime
sleepiness. Many published papers refer to OSA syndrome (OSAS) to describe
obstructive respiratory events in the presence of daytime hypersomnolence. Because
OSA can be detected overnight in patients who do not report sleepiness, the preva-
lences of OSA and OSAS differ substantially (discussed below). However, recent
research has highlighted the potential importance of “asymptomatic” OSA in terms
of cardiovascular risk leading some to question the utility of the OSAS term.
The gold-standard diagnostic test for OSA is full-night polysomnography (PSG)
where simultaneous measurements of cortical activity, eye movements and muscle
tone are made to determine sleep staging as well as respiratory airflow and effort,
pulse oximetry, and electrocardiography to identify respiratory and cardiac abnor-
malities. In situations where the use of full PSG is not feasible, a limited-channel
cardio-respiratory or oximetry study may also be used as diagnostic tools.
The main index by which OSA severity is judged is the apnea–hypopnea index
(AHI) – the number of apneas and hypopneas per hour of sleep. Limited-channel
recordings do not typically measure sleep/wake status and so use hours of recording
time for the denominator. Thus, if there is substantial time spent awake on such a
recording, the resulting AHI may be artifactually reduced. Nevertheless, the distinction
between an AHI based on hours of sleep or on hours of recording is often overlooked.

Clinical Definitions of Obstructive Sleep Apnea

The clinical definition of OSA is constantly evolving, and there is still no clear con-
sensus as to how to define the disease. There are a number of inconsistencies in PSG
methodology and the criteria used to score them, which makes comparisons of data
over time and between laboratories difficult.
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 93

In particular, the scoring criteria used to identify respiratory events are not widely
agreed upon. In 1997, a task force established by the American Academy of Sleep
Medicine (AASM) met in Chicago to develop consensus criteria for defining respira-
tory events and diagnosing OSA in order to facilitate comparability of studies for
research purposes [2]. These criteria, known as the Chicago criteria, were quickly
adopted by researchers around the world. However, an updated scoring manual
encompassing sleep stages, arousals and respiratory events was released by the AASM
in 2007 [3], and although it has become a requirement for sleep laboratory accredita-
tion in the United States, the Chicago criteria are still in widespread use internation-
ally (see Table 5.1 for a comparison of the Chicago and updated AASM criteria).
There are a number of key differences between the two sets of scoring rules. The
most notable difference is that the updated rules include two definitions of hypo-
pnea: the recommended definition is a reduction in thermal sensor amplitude of
³30% from baseline for ³90% of the event’s duration (³10 s) accompanied by a

Table 5.1 A comparison of respiratory event scoring according to Chicago 1999 and AASM 2007
criteria
Chicago criteria 1999 [2] AASM criteria 2007 [3]
OSAS Must fulfill A or B, plus C None
diagnostic A. Excessive daytime sleepinessa
criteria B. Two or more of the followinga
• Choking or gasping
• Recurrent awakenings
• Unrefreshing sleep
• Daytime fatigue
C. AHI ³5 events/h of sleep
Event Must fulfill A or B or C, plus D Must fulfill A or B or C, plus D
definitions A. Apnea A. Apnea
• >50% decrease in breathing • ³90% decrease in breathing
amplitude amplitude for ³90% of event
duration
B. Hypopnea B. Hypopnea
• A clear but <50% decrease in • Recommended: ³30% decrease
breathing amplitude, plus O2 in breathing amplitude for
desaturation >3% or an arousal ³90% of event duration, plus
O2 desaturation ³4%
• Alternative: ³50% decrease in
breathing amplitude for 90% of
event duration, plus O2
desaturation ³3% or an arousal
C. Respiratory effort-related arousal C. RERA: no change from Chicago
(RERA)
• Increasingly negative esophageal
pressure, terminated by a sudden
increase in pressure and an
arousal
D. ³10 s duration D. ³10 s duration
(continued)
94 J.P. Bakker et al.

Table 5.1 (continued)

Chicago criteria 1999 [2] AASM criteria 2007 [3]
Technical Pneumotachometer is considered Identification of apnea with thermal
aspects the gold standard for measuring sensors; identification of hypopnea
airflow. with nasal pressure. Identification
In its absence, two independent of RERAs with esophageal
respiratory measurements should be pressure, but nasal pressure or
recorded; highest recommendation is respiratory inductance plethys-
given to mography of chest and abdominal
nasal pressure and respiratory movement are valid alternatives
inductance plethysmography of
chest and abdominal movement.
RERAs must be identified using
esophageal pressure
Severity Syndrome defined as the more severe of None
A or B
A. Daytime sleepiness
• Mild (occurring during activities
requiring little attention)
• Moderate (occurring during
activities requiring moderate
attention)
• Severe (occurring during activities
requiring active attention)
B. Overnight monitoring
• Mild (5 to <15 events/h)
• Moderate (15 to <30 events/h)
• Severe (³30 events/h)
a
Not better explained by other factors

³4% O2 desaturation from baseline, or alternatively a ³50% reduction in thermal

sensor amplitude accompanied by a ³3% O2 desaturation from baseline or termi-
nated by an arousal. Thus, the recommended definition focuses only on desaturation
with no importance given to arousal from sleep. A recent study compared the AHI
for 328 patients when scored using the three definitions of hypopnea, and reported
that the median AHI obtained using the 2007 recommended and alternative criteria
were 30 and 60%, respectively, of the median AHI obtained using Chicago criteria
[4]. Hence, both the recommended and alternative hypopnea definitions of the 2007
AASM rules are stricter than the Chicago definition.
At present, there is no agreement as to the use of either nasal pressure or thermal
sensors to identify respiratory events. The Chicago rules recommend that in the
absence of a pneumotachometer, two independent measurements of airflow should
be used. The highest evidence-based recommendation is given to nasal pressure
and respiratory inductance plethysmography, though it is noted that limited data
were available on which to base a firm recommendation. Nasal pressure is often
preferred to thermistry due to its improved sensitivity; however, the specificity of
this technique has been minimally studied. In addition, thermistor is preferred to
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 95

nasal pressure for the distinction between hypopnea and apnea. More respiratory
events are detectable using nasal pressure [5], leading to a higher AHI than when
thermal sensors are used.
The Chicago criteria focus on OSAS and include excessive daytime sleepiness
as a component of the diagnosis whereas the 2007 AASM criteria do not mention
OSAS and focus on OSA alone. The proposition of expanding the diagnostic
criteria of OSA to include asymptomatic patients has gained popularity in recent
years, as there appears to be no significant difference in long-term cardiovascular
mortality risk between sleepy and nonsleepy patients [6]. However, the conse-
quences of asymptomatic OSA on other outcomes remain controversial [7, 8].
The updated 2007 scoring criteria do not include a definition of OSA severity;
in practice this means that the AHI severity thresholds detailed in the Chicago
criteria are often used with the updated AASM scoring rules, despite the fact that
the AHI will be markedly different depending on the methodology and scoring
approach adopted. Using the 2007 AASM criteria could result in a positive
Chicago diagnosis becoming negative in up to 40% of patients [4], emphasizing
the need for new normative values to be calculated using the more recent scoring
criteria. Conversely, the 2007 AASM rules allow for the diagnosis of asymptom-
atic OSA, leading to a far greater number of positive cases. Ideally, the clinical
definition of OSA should be chosen based on rigorous research demonstrating the
ability to predict adverse effects and positive response to treatment. At this stage,
however, there is insufficient evidence available for a consensus to be reached.
Moreover, AHI is poorly predictive of many OSA complications, leading to uncer-
tainty about severity criteria and generating interest in developing new outcome
measures [9, 10].

Prevalence

OSA represents a major public health burden, and yet there is little doubt that the
disease remains enormously under-diagnosed [11]. The most widely cited OSA
prevalence study is now outdated by over 15 years [12] and the prevalence of
obesity – a major risk factor for OSA – has increased markedly over the intervening
period [13]. Additionally, some of the methodological inconsistencies mentioned
above, most notably the use of the narrower definition of OSAS rather than OSA,
contributes to confusion about the true prevalence of this disorder.
Performing PSG studies in a research setting is costly; many epidemiological
studies using PSGs have small sample sizes, while larger studies have tended to use
alternative monitoring methods. The methodology of existing epidemiological stud-
ies has also differed in terms of sampling strategies, respiratory event definition, and
criteria for diagnosing OSA making combining international datasets impossible.
Given that the risk factors of OSA (discussed further below) can be more or less
common in certain areas of the world, it is perhaps more appropriate to consider
each epidemiological study individually (see Table 5.2).
 96

Table 5.2 Major OSA prevalence studies

Male
preva- Female
First author Population Total screened/ Age range Airflow Scoring Criteria for lence preva-
Region (year) location studied recorded (years) Methods measure rules OSA (%) lence (%)
North Young (1993) State 3,513/602 30–60 Questionnaire Thermocouple Modified AHI ³ 5 + 4.0 2.0
America [12], Wisconsin, employees Full laboratory + end-tidal Chicagoa symptoms
USA PSG CO2 AHI ³ 15 9.1 4.0
AHI ³ 5 24.0 9.0
Bixler (1998) General 4,364/741 20–100 Telephone interview Thermocouple Modified AHI ³ 10 + 3.9
[14], population; Full laboratory Chicagoa symptoms
Pennsylvania, males PSG OA/HI ³ 15 7.2
USA
Bixler (2001) [15], General 12,219/1,000 20–100 Telephone interview Thermocouple Modified AHI ³ 10 + 1.2
Pennsylvania, population; Full laboratory Chicagoa symptoms
USA females PSG OA/HI ³ 15 2.2
Europe Duran (2001) General 2,148/555 30–60 Home interview Thermistor Modified AHI ³ 5 + 3.4 3.0
[16], Basque population Four-channel Chicagoa symptoms
Country, monitoring AHI ³ 10 19.0 14.9
Spain at home
Full laboratory
PSG
Asia Ip (2001) [17], Office workers; 784/150 30–60 Questionnaire Thermistor Modified AHI ³ 5 + 4.1
Hong Kong, males Full laboratory Chicagoa symptoms
China PSG AHI ³ 5 8.8
Ip (2004) [18], Office workers; 854/106 30–60 Questionnaire Thermistor Modified AHI ³ 5 + symp- 2.1
Hong Kong, females Full laboratory PSG Chicagoa toms
J.P. Bakker et al.

China AHI ³ 5 3.7

 Male
preva- Female
First author Population Total screened/ Age range Airflow Scoring Criteria for lence preva-
5
Region (year) location studied recorded (years) Methods measure rules OSA (%) lence (%)
Kim (2004) [19], General 5,020/457 40–69 Questionnaire Thermistor Modified AHI ³ 5 + symp- 4.5 3.2
Ansan, Korea population Full laboratory Chicagoa toms
(n = 335) or home AHI ³ 5 27.1 16.8
PSG (n = 137)
Reddy (2009) [20], General 2,505/365 30–65 Questionnaire Thermistor Standard AHI ³ 5 + symp- 4.0 1.5
South Delhi, population (translated) Chicago toms
India Full laboratory PSG AHI ³ 5 13.5 5.5
South Tufik (2010) General 1,042/1,042 20–80 Home interview Thermocouple 2007 AASM AHI 5–15 + 40.6 26.1
America [21], Sao population Full laboratory PSG + nasal symptoms
Paulo, Brazil pressure or AHI ³ 15
AHI ³ 5 46.5 30.5
Australasia Bearpark (1995) General 486/294 40–65 Questionnaire None O2 desat AHI ³ 5 + symp- 3.1
[22], Busselton, population; Four-channel ³3% + HR toms
Australia males monitoring at home increase or AHI ³ 5 25.9
snoring
Mihaere (2009) General 705/358 30–59 Questionnaire None O2 desat AHI ³ 15 3.9 0.2
[24], population Four-channel ³4% + HR AHI ³ 10 7.0 1.4
Wellington, monitoring at home increase or AHI ³ 5 12.5 3.4
Obstructive Sleep Apnea: Epidemiology of Sleep Apnea

New Zealand snoring

a
Modified Chicago: Standard Chicago rules [2], but using 4% O2 desaturation to score hypopnea and no scored RERAs
97
98 J.P. Bakker et al.

North America

To date, two large USA-based OSA prevalence studies have been performed using
in-laboratory PSG methodology: the Wisconsin and Pennsylvania cohorts. Both
studies recruited predominantly Caucasian participants.
The Wisconsin Sleep Cohort Study was initiated in 1988 by sending a question-
naire based on general sleep patterns to state employees aged 30–60 years, and
using this to identify those who reported habitual snoring, snorting, breathing pauses
or episodes of loud snoring [12]. Out of the participants who returned the question-
naires (n = 3,513), all of those reporting the above symptoms were recruited into the
study proper, along with 25% of those who did not report these symptoms in order
to gain a population with adequate variance. This population (n = 625) went on to
have an overnight in-laboratory PSG, with nasal and oral airflow measured using
thermocouples and end-tidal CO2, respectively; data were obtained for 602 partici-
pants. The Wisconsin study took place before the publication of the Chicago crite-
ria; the scoring rules adopted were similar and have since been referred to as
“modified Chicago” – a 4% O2 desaturation to define hypopnea rather than 3%, and
RERAs not scored. The prevalence of OSAS defined as an AHI ³ 5/h as well as self-
reported daytime sleepiness was 2% in women and 4% in men, but including asymp-
tomatic participants (AHI ³ 5/h only), the overall prevalence was 9% in women and
24% in men. For moderate to severe OSA (AHI ³ 15/h), the prevalences were 4% in
women and 9% in men. Because thermistor but not nasal pressure was used to
define respiratory events, one would predict even higher prevalences if the study
was done with current technology.
The Pennsylvania cohort was first reported in 1998 using males only [14], and
later expanded to include data from females [15]. Looking at both studies com-
bined, 741 males and 1,000 females (all 20–100 years of age) were chosen to
undergo overnight PSG, with oronasal airflow measured using thermocouples. Prior
interviews by telephone allowed the researchers to select a stratified random sam-
ple, with those exhibiting a greater number of risk factors being over-represented.
Using the same scoring rules as the Wisconsin study, a diagnosis of OSAS required
an AHI ³ 10/h as well as the presence of adverse daytime symptoms; using these
criteria an adjusted prevalence of 1.2% in females and 3.9% in males was found.
Using a different set of criteria (an obstructive AHI ³15/h; the mean number of
obstructive apnea/hypopnea events per hour of sleep, slightly different from the
definition of AHI), 2.2% of females and 7.2% of males were identified as having
OSA. Regardless of the diagnostic criteria, then, the Pennsylvania cohort studies
found a male:female OSA ratio of 3.3:1.

Europe

A Spanish cohort study published in 2001 used portable, home-based cardio-

respiratory monitoring as the basis of selection for laboratory-based PSG, with
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 99

oronasal airflow measured using thermistors, for 324 males and 231 females aged
30–70 years [16]. Again, this sample was predominantly Caucasian. Using modified
Chicago rules and the same threshold for defining OSAS as the Wisconsin cohort, this
study showed the prevalence of OSAS to be roughly similar to that found in North
America: 3.0% in females and 3.4% in males. When the criterion for disease was
reduced to simply an AHI ³ 10/h (without daytime hypersomnolence), the preva-
lence became 14.9% in females and 19.0% in males.

Asia

The first estimates of the prevalence of OSA in Asia were published in 2001 for
Chinese males (n = 150) [17] and 2004 for Chinese females (n = 106) [18]. Both
studies targeted 30- to 60-year-olds through offices and community centers, and all
subjects underwent laboratory-based PSG with oronasal airflow measured using
thermistors. The same criteria for identifying events as the aforementioned studies
were used. It was found that 2.1% of women and 4.1% of men, respectively, had
OSAS (an AHI ³ 5/h in the presence of excessive daytime sleepiness), while 3.7%
of women and 8.8% of men had OSA (AHI ³ 5/h) alone.
A study of 457 Korean participants aged 40–69 years found that 3.2% of women
and 4.5% of men reported excessive daytime sleepiness and exhibited an AHI ³ 5/h
obtained during either a laboratory- or home-based PSG using thermistors. Using
the criterion of AHI ³ 5/h alone, the prevalence increased to 16.8% in women and
27.1% in men [19].
Prevalence statistics based on PSG data from India were made available in 2009
[20]. Males and females aged 30–65 years were recruited and first completed a
questionnaire (n = 2,505), with a subset of these participants undergoing laboratory-
based PSG using thermistors for airflow measurement (n = 365). Using Chicago
scoring criteria, an AHI ³ 5/h in the presence of daytime sleepiness was observed in
1.5% of women and 4.0% of men; an AHI ³ 5 alone was observed in 5.5% of women
and 13.5% of men. The prevalence of OSA in Asia is therefore similar across China,
Korea and India, and comparable to that seen in other continents.

South America

The first South American study of OSA prevalence was published in 2010, based on
PSG data obtained from 1,042 Brazilian participants aged 20–80 years, of both
genders [21]. Airflow was measured with both nasal pressure and a thermocouple;
the updated AASM rules were used for scoring events, with hypopnea defined
according to the alternative criteria. 9.6 and 30.5% of women exhibited an AHI ³ 15/h
and AHI ³ 5/h, respectively; using the same cut-off thresholds, the prevalence data
in men were 24.8 and 46.5%. OSAS was defined as an AHI of 5–14.9/h in the presence
100 J.P. Bakker et al.

of loud snoring, daytime sleepiness, fatigue, and/or breathing interruptions, or an

AHI ³ 15/h regardless of other symptoms. Using this definition, the prevalence of
OSAS was 26.1% in females and 40.6% in males. All of these prevalences are much
greater than the figures seen in North America and other parts of the world. The
extent to which this difference reflects an increased risk for OSA among Brazilians
vs. much more liberal scoring criteria (use of nasal pressure and a 3% O2 desatura-
tion threshold to define hypopnea) is unclear.

Australasia

The only prevalence data available from the Australasian population come from two
studies utilizing four-channel home-based cardio-respiratory monitoring rather than
PSG. In an Australian study of 294 primarily Caucasian males aged 40–65 years,
26% had OSA defined as an AHI ³ 5/h, with a respiratory disturbance defined as an
O2 desaturation of ³3% occurring with either an increase in heart rate of ³10 beats
per minute, and/or snoring at the commencement and termination of the desatura-
tion, while 3.1% had OSAS [22]. A study of 364 New Zealanders (30–59 years old)
reported the prevalence of OSAS (AHI ³ 5/h and Epworth Sleepiness Scale [23]
score ³10/24) was 2.0% in Maori females, 0.7% in non-Maori females, 4.4% in
Maori males, and 4.1% in non-Maori males [24]. A respiratory disturbance was
defined using the same criteria as the Australian study, but used a 4% O2 desatura-
tion requirement. When the ethnic groups were combined, 3.4% of females and
12.5% of males had an AHI ³ 5/h alone. Thus, irrespective of definition used, the
ratio of male:female prevalence of sleep apnea is roughly 3:1 across continents and
ethnic groups.

Disease Progression

Of the prevalence studies using in-laboratory PSG methodology, the Wisconsin

sleep cohort provides data as to the progression of OSA as it was performed longi-
tudinally with baseline data collection (n = 948) followed by 4-year (n = 690) [13]
and 8-year (n = 282) [25] follow-ups. At baseline, 644 participants were identified
with an AHI < 15/h of which 39 (6%) went on to develop moderate-to-severe OSA
(AHI ³ 15/h) over 4 years [13]. Over 8 years, the 282 participants available for
follow-up showed an average AHI increase of 2.7 ± 8.2/h (from 2.5/h to 5.1/h), with
men and women having similar average increases (3.0 ± 9.4 and 2.3 ± 6.1/h, respec-
tively) [25]. Of note, there were a greater number of participants whose AHI
increased than decreased, and many participants with an AHI < 1/h showed an
increase to an AHI > 1/h whereas the converse was not true: few participants with an
AHI > 1/h showed a decrease to an AHI < 1/h.
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 101

Longitudinal data are also available from the Sleep Heart Health Study, a
multicentered, community-based cohort study based in the United States using
home-based PSGs conducted 5 years apart [26]. Data were available for 1,342 males
and 1,626 females aged ³40 years at baseline, with snorers oversampled.
Approximately 75% of the sample was Caucasian, 13% were Native American, and
6% were African-American. An apnea was defined as a ³10-s reduction in airflow
to <25% of baseline, and a hypopnea was defined as a ³10-s reduction in airflow of
<70% from baseline, with both measured using a thermocouple and requiring a
³4% O2 desaturation. The mean AHI increase over 5 years was 2.2 ± 9.0 in females
and 3.4 ± 12.4 in males with no differences identified across ethnicities.
Finally, the Cleveland Family Study published in 2003 performed four-channel
cardio-respiratory monitoring studies including oronasal airflow measured using
thermistors on 486 participants (78% Caucasian, 21% African-American, 2%
Hispanic/mixed ethnicity) at baseline and after 5 years [27]. Apneas and hypopneas
were scored when a cessation or reduction in airflow was observed accompanied by
an O2 desaturation of ³2.5%. Over the study period, the median AHI increased from
2.6 to 3.6/h; the prevalence of an AHI ³ 15 increased from 10.5 to 16.3%. Overall,
this evidence suggests a slow but steady progression in the AHI over time with rare
spontaneous improvements. Much of this deterioration is likely attributable to pro-
gressive weight gain (discussed further below).

Risk Factors

Obesity

The prevalence of obesity in both developed and developing countries has increased
markedly over the past few decades [28, 29], and represents a major crisis due to
deleterious outcomes including OSA. The high prevalence of obese and morbidly
obese patients in clinical OSA populations was recognized early, and there is now a
vast amount of evidence from community-based studies supporting this association.
In cross-sectional analyses, an increase in body mass index (BMI) of 1 standard
deviation (5.7 kg/m2) increased the risk of having an AHI > 5/h by 4.2-fold in the
Wisconsin cohort [12], and in the Sleep Heart Health Study a similar increase
(5.3 kg/m2) was associated with a 1.6-fold increased risk of having an AHI ³ 15/h
[30]. Based on data from the Wisconsin cohort, it has been estimated that 41% of all
OSA and 58% of moderate-to-severe OSA can be attributed to excess weight (BMI
³25 kg/m2) [31]. Epidemiological studies outside the United States have consis-
tently drawn similar conclusions [16–22, 24].
Further evidence comes from longitudinal analyses. The Wisconsin study
found that a 10% increase or decrease in weight over 4 years led to a greater
than 25% change in AHI in the same direction [13]. In addition, the increase in
AHI over 8 years was significantly larger in obese compared with nonobese
102 J.P. Bakker et al.

individuals [25]. The Sleep Heart Health Study and Cleveland Family Study
both reported that an elevated BMI was an independent risk factor for having a
greater increase in AHI at follow-up [27, 30]. In an untreated clinical sample, a
2009 study found that the mean change in BMI over 5 years was a strong predic-
tor of having a significant increase in AHI, defined as an increase of more than
five events per hour [32].
Moreover, weight loss achieved by surgery [33–35], caloric reduction and/or
exercise programs [36–39] can reduce OSA severity, though few of these studies
have been of a randomized controlled design. Significant weight loss has not
always equated to large AHI reductions as evidenced by the Sleep AHEAD study
in which the intervention group lost on average 10.8 kg but experienced a reduc-
tion in mean AHI from 22.9/h to only 18.3/h [40]. Data from the Sleep Heart
Health Study demonstrate that the increase in AHI associated with a given
increase in weight is greater than the decrease in AHI observed with weight loss
of the same magnitude [26]. This suggests that weight loss may be more effective
as a preventive measure than treatment of established OSA. There is also minimal
evidence as to whether the improvement in AHI is sustained once the interven-
tion has been withdrawn [36]. In fact, a number of studies have shown reemer-
gence of OSA following medical or surgical weight loss even without regain of
body weight. These data emphasize the need for ongoing clinical follow-up of
these patients.
Regardless, the overwhelming evidence from cross-sectional, longitudinal and
intervention studies indicates that the association between obesity and OSA is likely
to be causative, and there are a number of potential mechanisms. The most obvious
of these is a structural change of the pharyngeal airway induced by the accumulation
of fat in the upper airway region, leading to increased pharyngeal collapsibility (and
critical pressure) [41, 42], and possibly a mechanical decrease in lung volume [43].
A decrease in functional residual capacity may also reduce longitudinal tracheal trac-
tion, contributing to upper airway instability [44].
The multifactorial development of OSA as a result of obesity suggests that
different measures of body habitus may be more or less useful as predictors of AHI,
but this remains a controversial issue. The two main mechanistic proposals men-
tioned above have led to a focus on neck obesity (affecting the pharyngeal airway)
and central obesity (affecting lung volume). Neck circumference, tongue volume,
and pharyngeal wall volume are important risk factors of OSA [41, 45], and mea-
sures of central obesity such as waist circumference have been shown to be better
predictors of OSA than BMI [46]. Furthermore, AHI is more closely correlated with
intra-abdominal and subcutaneous abdominal fat measured by magnetic resonance
imaging than subcutaneous neck fat or pharyngeal fat [47].
Obesity is generally accepted as the most important predisposing feature for
OSA, particularly in Western populations, and because it is one of the only risk
factors that is readily reversible and doing so has other significant health advan-
tages, the role of obesity in OSA pathogenesis and its potential role as a target for
OSA treatments are areas of research receiving substantial attention.
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 103

Age

The first major community-based study of OSA in older populations (³65 years of
age) found that 70% of males and 56% of females had an AHI ³ 10 detected using
four-channel overnight monitoring [48] – markedly more than the prevalences in
middle-aged populations discussed above. This greater prevalence has been
confirmed in studies using full PSG – in a cohort of 461 females with mean age 83
years, 38% had an AHI ³ 15/h [49], and in a group of 2,849 males with mean age 76
years, 43% had an AHI ³ 15/h [50]. Even within an elderly cohort, the prevalence of
OSA appears to increase with age, as evidenced in a study of 2,911 males reporting
that 23% of those aged £72 years and 30% of those aged ³80 years had an AHI ³ 15/h
[51]. In the Spanish cohort, the odds ratio of developing OSA was 2.2 for each
decade increase in age [16].
Of course, any nonfatal disease is expected to become more prevalent with age as
the number of existing cases accrues. Whether older age is associated with a rise in
the incidence rate for OSA is unclear. It has been speculated that an increase in obe-
sity [29], changes in the anatomical structure of the upper airway [52, 53], a decline
in neural reflexes [52], or a greater contribution to the AHI from central sleep apnea
[14] may account for the increased prevalence of OSA in older populations.
An unanswered question is whether OSA in the elderly, unlike in younger popu-
lations, has adverse health consequences. Various cohort studies have found no
clinically significant association between OSA severity and sleepiness [49, 54] or
reduced neurocognitive capacity [54]. In the Sleep Heart Health Study, OSA was
only a risk factor for heart disease in those £70 years of age [55], and there is evi-
dence that moderate OSA may even confer a protective effect on mortality in those
³80 years [56]. Other studies, however, have reported contradictory results [51], so
the issue as to whether OSA in the elderly represents a separate clinical entity to that
seen in the middle-aged remains in dispute.

Gender, Menopause, and Pregnancy

Male gender is considered to be a risk factor for OSA as every large epidemiological
study published to date has found an increased prevalence of OSA in males [12,
14–21, 24], mostly within the range of 2:1–3:1. The gender discrepancy in clinical
studies is higher than that seen in community-based studies, indicating that females
are under-diagnosed in clinical practice. Clinicians may overlook women with
symptoms of OSA simply because they do not fit the picture of a typical patient, and
women may be more reluctant than men to report snoring, instead emphasizing
other symptoms such as insomnia [57]. There is also some evidence that female
bed-partners report a larger decrement in quality of life of their male partner with
OSA than vice versa [58], which may prompt a higher number of referrals for male
patients initiated by their partners. Despite this, it has been reported that female
104 J.P. Bakker et al.

OSA patients use healthcare resources significantly more than severity-matched

men, possibly due to lower perceived health status [59].
Several studies have investigated the effects of gender further by incorporating
menopausal status. Menopause was a significant risk factor for having an AHI ³ 5/h
and ³15/h after controlling for age, obesity, presence of cardiovascular disease, and
alcohol/cigarette consumption in the Wisconsin cohort [60]. In the Pennsylvania
cohort, postmenopausal women had a significantly higher prevalence of OSA than
premenopausal women (1.9 and 0.6%, respectively) [15]. Postmenopausal women
receiving hormone replacement therapy have similar prevalence rates to premeno-
pausal women [15], and lower prevalence rates than postmenopausal women not
receiving hormones [61]. Considered alongside the evidence that the prevalence of
OSA is similar between males and females in the pediatric population, and between
postmenopausal women not receiving hormone replacement therapy and adult
males [15], these data suggest that there may be a protective effect of estrogen and/
or progesterone in women of reproductive age relating to the enhancement of venti-
latory control [62, 63]. Administration of estrogen to postmenopausal women can
significantly lower the AHI [64, 65], but only one of these studies found a further
benefit after additional administration of progesterone [65]. However, the effect of
hormone replacement therapy on cancer and cardiovascular risk does not support its
routine use for OSA.
Pregnancy appears to induce snoring and symptoms indicative of OSA [66–69],
occurring to a greater extent in women experiencing large increases in neck circum-
ference [69]. Pregnant women have smaller upper airway diameters compared with
nonpregnant women, and experience a significant increase in upper airway size fol-
lowing childbirth [68]. Snoring and witnessed apnea are closely associated with
hypertension during pregnancy after controlling for a number of known confound-
ers [70] and may also lead to deleterious outcomes for the fetus [67, 71], emphasiz-
ing the need to closely monitor pregnant women for the development of OSA,
particularly those who were obese pre-pregnancy [72].
Apart from hormonal influences, the major factors accounting for the gender dif-
ference in OSA are probably related to differences in craniofacial structure [73–75],
upper airway length [76, 77], and body habitus.

Craniofacial Features

The pharyngeal airway – the segment comprised of the nasopharynx, velopharynx,

oropharynx, and hypopharynx – is a skeletal enclosure containing various soft tissues
responsible for multiple functions including swallowing, speech, and breathing. Both
the size and position of the bony structures and soft tissues can influence upper
airway size and the propensity for collapse. In addition, pharyngeal airway length is
important as a longer airway is more collapsible than a shorter one [76, 78].
Soft tissues of the upper airway include the pharyngeal muscles, tongue,
uvula, tonsils, soft palate, pharyngeal fat pads, and lateral pharyngeal walls.
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 105

Abnormal enlargement of any of these tissues through hypertrophy, inflammation,

or edema will produce a narrowing of the lumen. It has recently been highlighted
that the volume of upper airway soft tissue proportional to the cross-sectional cran-
iofacial area should be considered in assessing OSA risk [79]. A simpler approach
for risk stratification that can be readily utilized in the clinical setting is use of the
Mallampati score. This grading of oropharyngeal crowding is predictive of OSA
severity independent of overall neck circumference [80].
Skeletal structures of the pharyngeal airway include the nasal concha, maxilla
and mandible, hyoid, and the cervical vertebrae. Abnormal positioning of these
bones, primarily maxillomandibular retropositioning and inferior placement of the
hyoid, will encroach on the space available for the lumen regardless of the size and
position of soft tissues. Retrognathia assessed by cephalometry has been shown to
occur in OSA patients to a greater extent than controls [81]. Similarly, a more
collapsible airway measured by endoscopy is associated with a smaller maxilla and
mandible [42]. The ratio of maxilla to mandible size and maxilla to facial width may
also be important [82].
In humans, the hyoid is free-floating to allow speech, rather than being attached
to the cervical spine. This makes the upper airway less rigid than that seen in other
mammals and therefore more susceptible to collapse, particularly with the addi-
tional force of gravity while in the supine position. Many have suggested that this
could be one reason why OSA is an almost exclusively human condition [83]. The
distance from the posterior nasal space to the hyoid correlates positively with
pharyngeal collapsibility [84], and lower placement of the hyoid may potentially
predict AHI [85].
Although craniofacial abnormalities can sometimes be subtle and therefore
difficult to detect in the usual clinical setting, it is possible that craniofacial pheno-
typing through photographic analysis [86, 87] or imaging techniques [88] could be
used to predict accurately the presence of OSA and/or a positive response to treatment
by mandibular advancement [89].

Ethnicity

As mentioned, the major OSA prevalence studies from the United States [12, 14,
15], Europe [16] and Australia [22] have recruited predominantly Caucasian sam-
ples, making the worldwide distribution of OSA and any ethnic disparities difficult
to elucidate. What data do exist suggest that the prevalence of OSA in Asian popula-
tions is similar to that in United States and European Caucasians [17–20], although
at a lower level of obesity.
Because obesity tends to be more prevalent in minority groups, OSA may be
expected to be more common amongst these groups. This appears to be the case in
relation to Native Americans in the United States. In the Sleep Heart Health Study,
Native Americans were 70% more likely than Caucasians to have an AHI > 15/h,
but this difference disappeared after adjustment for differences in obesity [30].
106 J.P. Bakker et al.

Similarly, in a New Zealand study, those of Maori heritage were 4.3 times more
likely to have an AHI ³ 15 than non-Maori, but once BMI was controlled for ethnicity
was no longer an independent risk factor [24]. A number of studies have examined
whether independent of obesity, African-Americans may be at elevated risk for
OSA compared to Caucasians. While studies suggest that both young and elderly
African-Americans may be at greater risk [90, 91], no increased risk has been iden-
tified in middle-aged individuals [30].
In contrast, a wealth of data suggests that for the same level of obesity, Asians are
at greater risk of OSA than other groups. For example, while OSA prevalence is
similar in China [17, 18], Korea [19] and India [20] to that seen in the United States
[12, 14, 15], the mean BMI is substantially greater in U.S. cohorts. In addition,
Asian subjects may present with more severe disease [92]. Given the lower preva-
lence of obesity throughout Asia, it is likely that risk factors for OSA other than
obesity are particularly common among Asians. Asians appear to have a signifi-
cantly more crowded oropharynx, and significantly shorter thyromental distance
than Caucasians [93]. Similarly, another study found that Chinese participants had
a higher degree of bony restriction as measured by cephalometry than Caucasians
[94]. Craniofacial differences have been shown to exist within the Asian community
(comparing Malay, Indian, and Chinese subjects [95]), indicating that different ana-
tomical measurements may be more relevant in some groups than others. Similarly,
despite having similar overall risks for OSA, comparative data suggest the relevant
craniofacial risk factors for OSA likely differ in Maori and African-Americans
compared to Caucasians [96–98].

Alcohol and Cigarette Consumption

Regular intake of both alcohol and cigarettes have been associated with snoring and/
or OSA in univariate analyses of some [19, 20, 22, 24] but not all [17] observational
studies, which have relied on subjective reporting of consumption.
Only one study has reported that habitual alcohol consumption in males is asso-
ciated with an increased risk of OSA after adjustment for age, measures of body
habitus, smoking and medication use, but no association was found in females [99].
Randomized studies indicate that moderate alcohol consumption can significantly
increase the AHI in snoring volunteers [100] and the O2 desaturation index in
patients with established OSA [101]. Possible mechanisms for this effect include
the reduction of respiratory motor control and/or a blunted chemoreceptor-initiated
response to hypoxia.
Habitual snoring is significantly more prevalent in current-, ex- and even
passive-smokers compared with never-smokers, after controlling for age, gender
and BMI [102]. Data collected from a registry of male twins indicate that this asso-
ciation may not hold for more clinically significant OSA [103], although cessation
is still recommended given the recent emergence of evidence that smokers with
OSA are at a higher risk of cardiovascular complications than controls matched for age,
5 Obstructive Sleep Apnea: Epidemiology of Sleep Apnea 107

gender, BMI, OSA severity and presence of cardiovascular disease [104]. It is

possible that cigarette smoking may cause snoring due to inflammation of the upper
airway, but at this stage the mechanistic evidence is weak and should be a focus of
future research.

Familial/Genetic Factors

OSA clearly runs in families. Compared to an individual with no relatives with

OSA, having one relative with OSA increases one’s own risk of disease 1.6-fold
[105]. The risk further increases with a greater number of affected relatives – the
risk is 2.5-fold greater if one has two relatives with OSA and 4.0-fold greater if one
has three relatives with OSA. The heritability of the AHI has been found to be
30–35% in several studies suggesting one-third of the variability in this measure is
explained by shared familial factors [106–108]. Many of the risk factors for OSA
including obesity and craniofacial shape are known to have a genetic basis and this
may explain the familial nature of OSA. About 40% of the total genetic variance in
the AHI is explained by obesity [109] leaving the majority of the genetic basis for
OSA explained by obesity-independent factors such as alterations in ventilatory
control. In support of this notion, individuals with OSA are more likely to have a
child with sudden infant death syndrome (SIDS), a disease characterized by reduced
ventilatory drive [110, 111].
Genetic studies have suggested that OSA is a complex disease with multiple
susceptibility genes each with small to moderate effect [106, 107]. Although numer-
ous polymorphisms have been reported in the literature to predict OSA, these find-
ings have been inconsistent. To date, no polymorphism has been definitively
identified as a risk factor for OSA.

Summary of Keypoints

• There is an absence of international agreement as to how to define obstructive

respiratory events, and what should constitute a clinical diagnosis of OSA.
• The most widely cited prevalence study from the Wisconsin Sleep Cohort found
that 24% of middle-aged males and 9% of middle-aged females have OSA based
on an AHI ³5 events/h with or without daytime symptoms.
• Longitudinal studies suggest a slow but steady increase in disease severity over time,
particularly in association with weight gain, with rare spontaneous improvements.
• Obesity has been consistently identified as the most important reversible risk
factor for OSA, with evidence from cross-sectional, longitudinal and interven-
tional studies suggesting a causative link.
• The gender discrepancy in clinical studies is higher than that seen in community-
based studies, indicating that females are under-diagnosed in clinical practice
potentially due to referral bias or gender differences in symptoms.
108 J.P. Bakker et al.

• Both the size and position of the pharyngeal bony structures and soft tissues can
influence upper airway size and the propensity for collapse.
• Most ethnic differences in OSA prevalence can be explained by obesity. However,
prevalence rates in Asia are similar to those in North America and Europe but at
a lower level of obesity, suggesting additional risk factors in Asian groups.
• Genetic studies have suggested that one-third of the variability in OSA severity
can be explained by shared familial factors.

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Chapter 6
Obstructive Sleep Apnea: Clinical Features
and Adverse Consequences

Geraldo Lorenzi-Filho and Pedro Rodrigues Genta

Keywords Obstructive sleep apnea • Clinical features • Signs • Symptoms

• Cardiovascular consequences • Metabolic disorders

Introduction

Obstructive sleep apnea (OSA) is a disorder characterized by repetitive episodes of

partial or total upper airway obstruction during sleep resulting in hypopneas or
apneas, respectively. The episodes of upper airway obstruction result in exaggerated
intrathoracic pressure swings, asphyxia (characterized by hypoxemia and hypercapnia),
and fragmented sleep. The typical signs of OSA include loud and irregular snoring
and disturbed sleep due to the multiple arousals and awakenings. The typical patient
with OSA complains of nonrestorative sleep and daytime tiredness and/or excessive
sleepiness. However, a large number of patients may deny or actually not have typical
symptoms. There is growing recognition that OSA is tightly associated and may
contribute to several cardiovascular diseases, including hypertension and atrial
fibrillation. OSA syndrome is a denomination reserved for patients that present with
OSA plus associated symptoms, including sleepiness and/or cardiovascular disease.
The repetitive episodes of apneas or hypopneas represent a stress that can result or
contribute to cardiovascular and metabolic diseases. It is now recognized that severe
OSA is independently associated with poor cardiovascular outcome, including
myocardial infarction, stroke, and death from cardiovascular cause.

G. Lorenzi-Filho (*) • P.R. Genta

Pulmonary Division, Heart Institute (InCor), University of São Paulo School
of Medicine, São Paulo, Brazil
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 115
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_6,
© Springer Science+Business Media, LLC 2012
116 G. Lorenzi-Filho and P.R. Genta

Fig. 6.1 Polysomnography report of a patient with severe obstructive sleep apnea (apnea–hypopnea
índex = 87 events/h). (H) Hypnogram showing a fragmented sleep with multiple awakenings and
arousals; (P) body position; (SpO2) oxygen saturation. The figure in the bottom part shows a 3-min
recording of a few channels: EEG (C3-A2), respiratory monitoring by thorax and abdomen belts,
nasal cannula, oximetry and pulse derived from oximetry. The patient is presenting with multiple
obstructive events characterized by absence of airflow (nasal cannula) with continued effort to
breathe depicted by the movements in thoracic and abdominal belts. Observe the profound oxygen
desaturations associated with the obstructive events. The delay between the end of the respiratory
event and the nadir in oxygen saturation is due to circulatory delay (SpO2 was measured at the
finger tip) and the delay in oximeter signal

Overnight full polysomnography (PSG) is considered the gold standard method

for diagnosis and classification of OSA severity. The PSG of a patient demonstrating
repetitive episodes of apneas is presented in Fig. 6.1. The primary consequences of
OSA include: (1) Recurrent episodes of asphyxia (hypoxemia + hypercapnia);
(2) Exaggerated negative intrathoracic pressure; (3) Arousals from sleep resulting
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 117

in fragmented sleep. These respiratory events (i.e., apneas or hypopneas) may

impact on the macro structure of sleep, resulting in loss of restorative sleep, includ-
ing slow wave and rapid eye movement (REM) sleep. The main metric derived from
PSG is the number of apneas + hypopneas/h of sleep (AHI). AHI < 5 events/h is
considered normal, while AHI 5–15, 16–30 and > 30 events/h is consistent with
mild, moderate and severe OSA, respectively.

Risk Factors for OSA

Because some patients may not readily report their symptoms or be minimally
symptomatic, OSA is frequently under-recognized in clinical practice. Therefore,
it is important to determine which groups of patients are at increased risk for
OSA. The risk factors for OSA are to some extent linked to the pathophysiology
of OSA. While awake, dilator muscles stiffen and dilate various regions of the
upper airway, keeping it patent. Their activity is reduced during sleep, leading to
narrowing of the upper airway. In addition to the upper airway dilator muscle
activity during sleep, a number of factors are known to contribute to the pathogen-
esis of OSA, including, upper airway anatomy, lung volume, ventilatory control
stability, sleep state stability, and rostral fluid shifts. The relative contributions of
each factor may vary between individuals. The main risk factors associated with
OSA are listed below.

Obesity

Increased soft tissue, as is found in obesity, is the main factor for reduced upper
airway lumen and OSA. Obesity is postulated to cause OSA via mechanical effects
on airway size. In addition, obesity may also affect upper airway patency indirectly
through changes in lung volume and neural effects that blunt the neuromuscular
response. Lower end-expiratory lung volume, as occurs in the setting of obesity,
increases the tendency of the upper airway to collapse. This effect is thought to be
mediated by the decreased “tug” of the trachea, which stiffens and dilates the upper
airway as lung volumes increase. Independent of the exact mechanism, obesity is a
strong risk factor for OSA. Among patients with OSA, 70% are overweight or
obese. In the Sleep Heart Health Study the prevalence of moderate to severe OSA
was threefold higher in the highest quartile of body mass index (BMI), relative to
the lowest. In clinical practice, a BMI > 30 kg/m2 should be regarded as a risk factor
for OSA. For instance, approximately 30% of patients with a BMI greater than
30 kg/m2 have OSA and 50% of patients with a BMI greater than 40 kg/m2 have
OSA. Therefore, independent of the reasons for clinical evaluations, obese patients
should be carefully evaluated for other traits and symptoms suggestive of OSA.
118 G. Lorenzi-Filho and P.R. Genta

Age

The prevalence of OSA has been shown to increase with age in adults, up to age 65.
This age-related increase has been attributed to parapharyngeal fat deposition, soft
palate-lengthening, and changes in other parapharyngeal structures. Some authors
have suggested that the clinical presentation of OSA in the elderly is different and
that the cardiovascular consequences may be less severe. In the Sleep Heart Health
Study, sleep disordered breathing in older people was poorly predicted by obesity,
neck circumference, and self-reported apneas.

Sex

OSA is more common in males than in females. The male predominance in OSA preva-
lence is related to sex-related differences in upper airway anatomy and function, obesity
and fat distribution, ventilatory control, and hormonal status. Most population-based
studies have found a two to threefold higher prevalence of OSA in males than in females.
The ratio of men to women diagnosed in sleep centers is even more skewed toward men,
with reported ratios of 8:1 and higher. There is therefore a tendency to under-diagnose
women in clinical practice. Women may present with less severe OSA, report nonspe-
cific symptoms more frequently which may lead clinicians to consider other diagnoses.
Among males, the most important risk factor for OSA is obesity. In contrast, women are
relatively protected from severe OSA. After menopause, the prevalence of OSA rises
dramatically. Therefore, among women, the most important risk factor for severe OSA
is age. Women frequently present with “atypical” symptoms, and do not complain of
EDS, but of tiredness, lack of energy, and symptoms that overlap with depression.

Ethnicity

Some ethnic groups may be at greater risk for OSA. For example, African-Americans
present a higher risk for OSA than Caucasians. Recent studies have suggested greater
severity of OSA among Asians as compared to Caucasians controlled for BMI.
Conversely, Asians are leaner than Caucasians when AHI is paired. Taken together,
these data suggest that Asians are predisposed to developing OSA. Differences in
craniofacial anatomy have been proposed to explain this apparent propensity to OSA
among Asians as compared to Caucasians. One alternative explanation is that the
comparison of BMI among Asians and Caucasians is misleading and does not capture
differences in body composition. Asians have more body fat at lower BMI than
Caucasians. The World Health Organization recognizes these differences and proposes
different BMI cut-offs to define obesity according to ethnic group. A BMI ³ 25 kg/m2
should be used to define obesity in Asian populations, which contrasts with the
definition for all other groups (BMI ³ 30 kg/m2). Therefore, a higher fat deposition for
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 119

any BMI helps to explain why OSA is common in apparently lean Asians. Supporting
this hypothesis, epidemiological studies showed a similar prevalence of OSA in Asian
populations and Americans. In clinical practice, one must have in mind that a lower
BMI threshold (BMI > 25 kg/m2) should be used as the cut-off for defining obesity
among Asians.

Bony Structures

The bony enclosure (skull) interacts with soft tissue structures to determine upper
airway collapsibility. A small maxilla and mandible are extremely important and will
be addressed later on in this chapter in the topic “physical examination.” Although
obesity is one of the main risk factors for OSA, OSA is extremely common and many
patients with OSA are actually lean. In this group of patients, subtle alterations in
bony structure, such as a small mandible or arched palate frequently is present and
helps to explain the small airways and propensity to collapse during sleep.

Diseases Associated with Edematous States

Fluid shifts from the legs to the neck appear to play a role in the pathogenesis of
OSA. Fluid displacement from the legs caused by lower body positive pressure has
been shown to reduce upper airway size and increase collapsibility in healthy awake
subjects. Further, overnight rostral fluid displacement from the legs was found to be
correlated strongly with AHI, change in neck circumference, and time spent sitting,
in nonobese, healthy men suspected of having OSA. This mechanism may explain
the finding that lack of exercise is associated with increased severity of sleep disor-
dered breathing, independent of measures of body habitus. Greater time spent in
sedentary activity may increase lower leg edema and result in more sleep-related
fluid shift to the upper airway. From the clinical point of view the most important
message is that patients with diseases that may trigger edematous states, such as
renal failure and congestive heart failure are at increased risk of OSA at a lower BMI.
Despite being lean, the prevalence of OSA among patients with chronic renal failure
under dialysis and in patients with congestive heart failure is strikingly high. Patients
with congestive heart failure are at increased risk of both central sleep apnea associ-
ated with Cheyne–Stokes respiration as well as OSA. The reasons for central sleep
apnea in patients with congestive heart failure are beyond the scope of this chapter.

Positive Family History

Relatives of patients with OSA have a two to fourfold increased risk of OSA com-
pared with control subjects. The reason for this aggregation is multiple and includes
120 G. Lorenzi-Filho and P.R. Genta

inherited craniofacial characteristics, propensity to obesity, and probably other factors

such as control of ventilation, regulation of inflammation and upper airway muscle
control. Several candidate genes that may help to explain the propensity to OSA are
under investigation. From the practical point of view, first relatives of a patient
recently diagnosed with OSA must be advised of the increased risk of having the
disease. Conversely, patients seeking medical attention should be asked if they have
relatives with OSA.

Hypothyroidism

OSA is more prevalent among patients with hypothyroidism. Hypothyroidism leads

to the accumulation of hialuronic acid in the skin and subcutaneous tissue that
provokes the enlargement of tongue and pharyngeal mucosa. In addition, hypothy-
roidism may lead to a decrease in central ventilatory drive.

Presence of Co-Morbid Conditions

OSA is tightly linked to several cardiovascular and metabolic diseases, including

hypertension, atrial fibrillation, diabetes, stroke, congestive heart failure, and meta-
bolic syndrome. These conditions will be discussed in the last part of this chapter
(consequences of OSA). It is important to note that the prevalence of OSA among
these patients is much higher than in the general population. Moreover, several of
these patients do not report typical symptoms. Therefore, having one of these condi-
tions is a risk factor for OSA.

Clinical Symptoms

Patients with OSA frequently do not report their symptoms. The main reason is that
the patient is not aware of what is happening to him/her during sleep. In addition,
patients with OSA may not perceive themselves as being “sleepy.” Therefore, a
careful interview as well as collateral information from a bed partner is extremely
important. The symptoms associated with OSA may be divided in night, morning,
and daytime (Table 6.1). The overnight symptoms include frequent, loud, disturbing,
and irregular snoring. Witnessed apneas are the most specific symptoms associated
with OSA. It is remarkable that most patients are not aware of their sleep problems.
Several patients rate themselves as “good sleepers.” A subgroup of patients with
OSA may complain of insomnia with difficulties in initiating and maintaining sleep.
Insomnia is more common in women and in patients with mild to moderate forms
of OSA.
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 121

Table 6.1 Symptoms associated with OSA

Period Symptom Comments
S Loud snoring Less specific is elderly population
L Witnessed apneas One of the most specific symptoms, overlaps with
E central apnea
E Choking Overlaps with laringospasm
P Dry mouth Unspecific
Nocturia Unspecific
Restless sleep Patients are frequently not aware
Insomnia More common in mild OSA
M O R N I NG Nonrefreshing sleep Commonly reported
Headache Unspecific
D Sleepiness Frequent in patients referred to sleep clinics
A Tiredness Frequent among womena
Y Memory loss Unspecific
Sexual impairment Frequently not reported
a
Women more frequently complain of unspecific symptoms such as fatigue, irritability, decreased
energy, headaches, chronic muscle pain, and other depressive symptoms

Patients typically complain of daytime somnolence with drowsiness, particularly

during “passive situations” such as after meals, while watching television, or attending
a lecture. The hallmark daytime symptom of OSA is excessive daytime sleepiness
(EDS). EDS is thought to be related to the fragmented and nonrestorative sleep.
The most popular form to assess EDS is through the Epworth Sleepiness Scale.
This is a self-administered scale in which the patient rates his/her probability of
doze off (0–3) in eight different situations typical of daily life (Fig. 6.2). The scale
therefore may vary from 0 to 24 and scores > 10 are compatible with EDS. Patients
with OSA may not complain of EDS but may report tiredness. Fatigue, irritability,
decreased energy, headaches, chronic muscle pain, and other depressive symptoms
are more common in women. However, several patients with OSA are minimally
symptomatic and may deny or report no symptoms. In this group of minimally symp-
tomatic patients treatment may be justified on the basis of prevention of the cardio-
vascular, metabolic consequences of OSA.

Physical Signs

The most common physical sign associated with OSA is obesity, as characterized
by a BMI > 30 kg/m2 in Caucasians and BMI > 25 kg/m2 in Asians. Central obesity
is a more specific risk factor for OSA, and can be measured in clinical practice by
neck and waist circumferences. The cut-off points for large neck circumference
most used are > 17 in. (43 cm) and 16 in. (41 cm) in males and females, respectively.
122 G. Lorenzi-Filho and P.R. Genta

How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just
tired? This refers to your usual way of life in recent times. Even if you have not done some of
these things recently try to work out how they would have affected you. Use the following scale
to choose the most appropriate number for each situation:
Situation Chance of dozing
0 1 2 3
Sitting and reading

Watching TV

Sitting inactive in a public place (e.g a theater or a meeting)

As a passenger in a car for an hour without a break

Lying down to rest in the afternoon when circumstances permit

Sitting and talking to someone

Sitting quietly after a lunch without alcohol

In a car, while stopped for a few minutes in traffic

0 = no chance of dozing
1 = slight chance of dozing
2 = moderate chance of dozing
3 = high chance of dozing

Fig. 6.2 Epworth sleepiness scale

Large waist circumference should be considered as the same as that used for metabolic
syndrome > 40 in. (102 cm) and > 35 in. (88 cm) in males and females, respectively.
Among Asians these cut-off points are reduced to 35 in. (88 cm) and 31 in. (79 cm)
in males and females, respectively.
Overweight and obesity are present in approximately 70% of the patients with
OSA. However, because OSA is very common in the general population, a large
number of patients with OSA have normal weight. As stated earlier, only 50% of
patients with a BMI > 40 kg/m2 have OSA, clearly indicating that other factors play
a role in the genesis of OSA. The other physical signs associated with OSA are
directly related to upper airway anatomy and must be carefully evaluated. A crowded
pharynx is one of the most common physical signs associated with OSA. It can be
assessed by the modified Mallampati score proposed by Friedman. The other physical
signs associated with OSA include lateral narrowing of the posterior pharynx,
enlargement of the uvula, tongue and tonsils. Other physical signs that may also
help to recognize patients at high risk for OSA include retrognathia, overjet, and
arched palate.
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 123

Adverse Consequences of OSA

Consequences Directly Linked to Symptoms

The symptoms that frequently are the motive for patients with OSA to seek medical
attention are thought to be directly linked to the adverse consequences of OSA.
However, patients with OSA frequently have overlapping diseases that may explain,
at least in part some of the symptoms attributable to OSA. The best way to prove a
direct cause and effect relationship between OSA and an adverse consequence is to
observe the effects of the treatment OSA on a particular symptom. EDS, daytime
tiredness or fatigue is a common complaint of patients with OSA referred to sleep
centers. These symptoms are frequently dramatically improved after initiation of
treatment of OSA with CPAP. Drivers with OSA are at increased risk of motor
vehicle crash. Daytime sleepiness improves significantly following a single night of
OSA treatment with CPAP, and simulated driving performance improves signifi-
cantly within 2–7 days of treatment. Several studies have consistently shown that
there is a significant crash risk reduction following treatment of OSA with CPAP.
Cognitive impairment, including attention deficit, memory decline, and impaired
concentration and judgment has been associated with OSA. However, the reversion
of these symptoms with CPAP is less clear than the reversion of EDS. This does not
prove that OSA did not cause the disease. Central nervous system alterations caused
by OSA may be irreversible at the time of the diagnosis and treatment initiation.
The most likely explanation is that OSA causes microvasculature alterations in the
central nervous system and therefore not reversible changes. This mechanism may
also help explain the presence of residual EDS in several patients with OSA after
effective treatment with CPAP.

Cardiovascular and Metabolic Consequences

The prevalence of cardiovascular disease among patients with OSA is extremely high.
Conversely, among patients with established cardiovascular disease the prevalence of
OSA is much higher than in the general population and is estimated to be ~30%
among patients with hypertension, ~70% among patients with resistant hypertension,
~50% among patients with atrial fibrillation, ~ 30% in patients with coronary artery
disease, and ~50% among patients with type 2 diabetes. One plausible explanation is
based on the fact that OSA and all above-mentioned cardiovascular diseases share
several risk factors including obesity, male sex, increasing age, and sedentary lifestyle.
In addition to this explanation, there is good evidence that OSA may contribute to
cardiovascular and metabolic deregulation. The pathways triggered by OSA that are
potentially harmful to the cardiovascular and metabolic system are multiple and
include increased sympathetic activity, oscillations in blood pressure, oxidative stress,
124 G. Lorenzi-Filho and P.R. Genta

systemic inflammation, insulin resistance, dyslipidemia, and endothelial dysfunction.

Patients with OSA may have activation of neutrophils and monocytes with increased
production of reactive oxygen species, and expression of adhesion molecules and
enhanced cytokines production, including interleukin 6 and tumor necrosis factor
alpha. Many study, although not all, have shown that patients with OSA have elevated
C-reactive protein levels that may be attenuated with the treatment with CPAP.
There is increasing evidence that OSA may contribute to acceleration of atheroscle-
rosis, and that the treatment of OSA can revert this process. The activation of these
pathways may contribute to the development and aggravation of hypertension, heart
remodeling, atrial fibrillation, and diabetes. Patients with OSA are at increased risk for
development of heart failure, future myocardial infarction, stroke, and death from
cardiovascular disease. Distinct cohort drawn from patients referred to a sleep labo-
ratory in Spain, from the general population in Wisconsin, Busselton (Australia), and
the Sleep Heart Healthy Study showed consistently that severe OSA is independently
associated with risk of future cardiovascular death, mainly due to stroke and coronary
artery disease. The treatment of OSA with CPAP is also associated with a reduction in
cardiovascular mortality. However, these are observational studies and future random-
ized studies are necessary to fully elucidate if the treatment of OSA with CPAP is
able to reduce cardiovascular mortality. One relevant clinical aspect is that, in contrast
to patients referred to sleep laboratories, cross-sectional studies in patients with
established cardiovascular disease have consistently shown that these patients are
frequently minimally symptomatic. This observation further increases the importance
of answering the question whether the treatment of OSA will decrease future cardio-
vascular events in this group of patients.

Hypertension

Hypertension is the most studied and well documented link between OSA and
cardiovascular disease. Patients with OSA experience oscillations in blood pressure
that occur in concert with respiratory oscillations with peaks in blood pressure that
occur a few seconds after the termination of each respiratory event. These oscillations
occur in association with profound oscillations in sympathetic activity that peaks just
before the termination of each respiratory event. Patients with OSA tend to lack the
sleep-related nocturnal decrease in blood pressure (nondippers), present with masked
hypertension or overt hypertension. In addition to sympathetic overactivity several
other interrelated mechanisms may contribute to hypertension in patients with OSA
and include chemoreceptor stimulation, decreased barroreflex sensitivity, activation of
renin–angiotensin system, systemic inflammation, and endothelial dysfunction.
OSA and hypertension are tightly linked, making it difficult to prove a cause and
effect relationship in cross-sectional studies. OSA was independently associated
with an increased risk of developing future hypertension in both the Wisconsin
cohort study and the Sleep Heart Health Study. Several studies have shown a fall in
blood pressure after the treatment of OSA with CPAP. However, the magnitude of
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 125

the blood pressure fall is quite variable between studies. There are studies that
demonstrated that CPAP lowers blood pressure solely in patients with OSA plus
daytime sleepiness, but not in those with mild apnea or even severe disease with
only minimal clinical symptoms. The hypothesis that the effects on blood pressure
are nonexistent in patients without EDS has not been replicated in one large study.
However, when all studies are pooled together the overall fall in blood pressure after
CPAP is relatively small (~2 mmHg) and seems to be more pronounced in patients
with severe OSA and in patients with high and uncontrolled blood pressure at study
entry. There is also some evidence that the prevalence and effects of treatment on
blood pressure may be more evident among patients with resistant hypertension.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure recognizes OSA as an identifiable cause of hypertension.

Coronary Artery Disease

In the general population, the risk of developing acute coronary disease increases in
the first morning hours and is coincidental with a peak in the sympathetic activity.
In contrast, there is some evidence that OSA may predispose to nocturnal angina
that can be reverted with the treatment with CPAP. There is some evidence that
among patients with coronary artery disease, patients with OSA have more severe
coronary atherosclerotic disease than patients without OSA. There is also some
evidence that OSA is independently associated with subclinical coronary artery disease.
In the Sleep Heart Health Study, it was shown that OSA was an independent risk
factor for coronary artery disease. One observational study showed that patients
with OSA and coronary artery disease had lower mortality when OSA was treated
as compared to those not treated for OSA.

Stroke

Sleep-related breathing disorders are both a possible risk factor and a consequence
of stroke. Sleep apnea is very common following stroke (60–70%) and may in part
be a consequence of instability of respiratory drive to breath and central apneas.
There are several mechanisms by which OSA may contribute to increased risk of
stroke such as: hypertension, oscillations in blood pressure during respiratory events
with cyclic episodes of decreased cerebral blood flow, atherosclerosis progression,
increased platelet activity, and hypercoagulability. Observational cohort study
which followed patients who were referred for a sleep study found an increased risk
of stroke or death among patients with OSA. Prospective cohort studies have shown
that OSA is associated with increased risk of stroke. Similarly to what has been
previously described, patients with stroke frequently do not have the typical OSA
symptoms.
126 G. Lorenzi-Filho and P.R. Genta

Arrhythmias

Patients with OSA experience cyclic oscillations in heart rate, with progressive
bradycardia during apneas, followed by tachycardia that occurs in concert with
ventilation. The heart rate oscillations reflect autonomic instability and do not
represent a threat to the patient. Frequent ventricular ectopic beats, atrio-ventricular
blockade are more frequent in patients with OSA than in controls. Among patients
with heart failure and implantable cardioverter-defibrillator, the frequency of life-
threatening ventricular arrhythmia was higher among patients with sleep disordered
breathing and was more likely to occur during sleep. In another study, people with
OSA had a peak in sudden death from cardiac causes during the sleeping hours,
which contrasted strikingly with people without OSA that presented a peak of sudden
death from cardiac causes during the morning period. This study however did not
investigate the cause of sudden death and only reported on the timing of sudden
death, therefore not implying that OSA is associated with increased events.
The most relevant arrhythmia associated with OSA is atrial fibrillation. There are
several pathways that may help to explain the link between OSA and atrial fibrillation
and include heightened sympathetic neural activity, instability in autonomic tone,
and systemic inflammation. In addition, the thin-walled atria may be most vulnerable
to increased transmural forces experienced during obstructive events. The stressed
atria over time could contribute to chamber enlargement, a risk factor for atrial
fibrillation. Cross-sectional echocardiographic studies have consistently shown that
patients with OSA have higher left atrial volume indices than BMI-matched controls
without OSA.
Patients with atrial fibrillation have a high prevalence of OSA. In one study, the
recurrence of AF 1 year after electrical cardioversion occurred significantly less in
patients with OSA effectively treated with CPAP than in patients with OSA that
were not treated (42 vs. 82%). These data therefore, although not definitive, suggest
that OSA contributes to the genesis of atrial fibrillation and that the treatment of
OSA with CPAP may reduce the incidence of atrial fibrillation.

Diabetes and Metabolic Syndrome

According to the National Cholesterol Education Program–Adult Treatment Panel

(ATP III) metabolic syndrome is based on simple clinical findings that include
abdominal obesity, dyslipidemia, hypertension, and increased plasma glucose.
According to clinical and epidemiological studies, the cluster of risk factors known
as the metabolic syndrome is associated with increased risk for cardiovascular
events and mortality in the general population. The prevalence of OSA among
patients with metabolic syndrome is strikingly high (~70%) and because OSA
interacts and may aggravate all components of metabolic syndrome, it should be
incorporated as part of the syndrome. The Sleep Heart Health Study showed that
sleep-related hypoxemia was associated with glucose intolerance independently of
6 Obstructive Sleep Apnea: Clinical Features and Adverse Consequences 127

age, sex, BMI, and waist circumference. OSA severity was also associated with the
degree of insulin resistance after adjustment for obesity. The Wisconsin Sleep Study
demonstrated a significant cross-sectional association between OSA and type 2
diabetes for all degrees of OSA, which persisted for moderate-to-severe OSA after
adjustment for obesity. Despite the strong evidence indicating that OSA and type 2
diabetes are associated, the studies supporting a putative role for OSA in the devel-
opment of type 2 diabetes are limited. Moreover, some authors have proposed a
reverse direction of causality since autonomic neuropathy caused by diabetes could
generate disturbed control of respiration. The effects of CPAP treatment on glucose
metabolism have been evaluated in both nondiabetic and diabetic patients, with
controversial results. While some studies showed an improvement in insulin resis-
tance, others failed to show any significant effect. In type 2 diabetic patients with
OSAS, observational studies using continuous glucose monitoring techniques have
reported positive effects of CPAP on glycemic control. Another study showed that
postprandial glucose values were significantly reduced 1 h after treatment, and
HbA1c level decreased in patients with abnormally high baseline HbA1c. A retro-
spective study also confirmed a slight reduction in HbA1c in diabetic patients with
OSA treated with CPAP. However, a randomized controlled trial comparing thera-
peutic or placebo CPAP for 3 months found no difference in terms of glycemic
control or IR in these patients. In summary, the impact of obesity may offset the
impact of CPAP in patients with type 2 diabetes. Similarly, the effects of CPAP
treatment on the MetS are controversial. It is possible that OSA treatment may posi-
tively affect only some components of metabolic syndrome (such as blood pressure)
rather than affecting all of them.

Conclusion

OSA is extremely common in the general population and even more common among
specific populations of patients with high cardiovascular risk. The typical patient with
OSA is an obese, middle age male with loud snoring and excessive daytime sleepiness.
However, there is growing awareness that these several patients are not obese or are
minimally symptomatic. Women frequently complain of nonspecific symptoms such
as fatigue and depression like symptoms. The typical symptoms are also less common
in the elderly population. There is growing evidence that patients with OSA may be at
increased cardiovascular risk. OSA may trigger or contribute to several cardiovascular
disease, including hypertension, atrial fibrillation and congestive heart failure.

Summary of Keypoints

• In this chapter, the clinical features and adverse consequences of OSA are
reviewed. OSA is characterized by repetitive episodes of upper airway obstruc-
tion and is frequently found among adults.
128 G. Lorenzi-Filho and P.R. Genta

• Risk factors : Obesity is the major risk factor for OSA through mechanisms such
as fat deposition in the pharynx inducing airway narrowing and decreased tracheal
tug. OSA prevalence increases up to the seventh decade. Men have a two to
threefold higher prevalence of OSA than women in part due to central fat distri-
bution, higher pharyngeal length and ventilatory instability.
• Symptoms: Loud, frequent, and irregular snoring are the most significant symptoms
of OSA. Witnessed apneas is specific but is frequently not reported by the bed
partner. Excessive daytime sleepiness, once thought to be the most important
symptom of OSA, is only common among patients referred to sleep laboratories.
In contrast, excessive daytime sleepiness is not common among patients with
OSA and cardiovascular diseases as well as in community-based studies.
• Signs: Obesity is the most common sign of OSA and is more specific when centrally
distributed as can be measured by neck and waist circumference determinations.
A crowded pharynx as classified by the Mallampati scores III and IV is frequently
observed in patients with OSA.
• Consequences of untreated OSA include excessive daytime sleepiness, fatigue,
cognitive dysfunction, and impaired quality of life. OSA is frequently associated
with cardiovascular and metabolic disorders. This association is explained not
only by overlap of risk factors, such as obesity and male sex, but by the fact that
OSA contributes to the development and aggravation of the underlying cardio-
vascular and metabolic diseases. Hypertension is the most studied cardiovascular
consequence of OSA. OSA is now a recognized cause of secondary hypertension.
In addition, OSA may contribute to arrhythmias, heart failure, insulin resistance,
diabetes, dyslipidemia, and atherosclerosis progression. Untreated severe OSA
is associated with increased risk of cardiovascular morbidity and mortality due
to coronary artery disease and stroke.
Chapter 7
Assessments of Driving Risk in Sleep Apnea

Kingman P. Strohl

Keywords Driving risk • Automobile crashes • Sleepiness • Fatigue • Impairment

Scope of the Problem

Sleepiness, also termed drowsiness, is defined by a set of neurocognitive behaviors

within the state of wakefulness. It is rapidly reversible as is sleep, in contrast to
states of stupor, coma, and anesthesia. Sleepiness in the wakefulness state can be
defined by an attenuation of general vigilance associated with slowing of reaction
times, not otherwise explained by neurologic or medical disease or exposure to
medication, alcohol, and illicit drugs. Excessive waketime sleepiness is a risk factor
to falling asleep abruptly, potentially with catastrophic consequences. One of the
direct, functional outcomes of excessive sleepiness is that of impairment in driving
performance and an increase in risk for drowsy driving and motor vehicle crashes,
including traffic fatalities.
Fall-asleep accidents are generally inferred by the following characteristics.
First, there is usually a pattern of drifting outside a lane to the right or left; second,
there are no skid marks or apparent attempt to avoid a crash; and third, there should
be no evidence for substance abuse [1]. Drug- or alcohol-related accidents can be
determined from biologic samples, while sleepiness cannot. Often, there is a single
driver. From compilation of records across several states and primary articles, sleep-
related accidents, defined as above, are highest in males between the ages of 16 and
26 years, presumably because of risk-taking and other behavioral factors, followed
by shift workers because of irregular and reduced sleep, and then by undiagnosed
sleep disorders, like sleep apnea and narcolepsy [2, 3].

K.P. Strohl (*)

Louis Stokes Cleveland DVA Medical Center, 10701 East Boulevard, Cleveland, OH, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 129
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_7,
© Springer Science+Business Media, LLC 2012
130 K.P. Strohl

a
60
58
56
54
Infraction %
N=69
Report of
52
50
48 N=204
46
44 N=345
42
40
b
5
% subjects with serious crash

0
SEVERE MODERATE ALERT
Multiple Sleep Latency Test Groups

Fig. 7.1 Impact of sleepiness in a community sample. Shown here are data from Drake et al. [4]
in two formats. The bars represent the groups according to MSLT category (see text) into severe
(MSLT: 0.0 to < or = 5 min), moderate (5–10 min), and alert (>10 min). In (a) (top), there is shown
the percent of subjects in each group where state driving records showed some traffic infraction or
crash. The numbers on each bar represent the number of individuals. There appears a dose–
response relationship (p = 0.48). In (b) (bottom), there is shown the number with severe injury
accidents, those which prevent normal activities and require hospitalization. The severe group is
significantly higher (p = 0.05) than the other groups

Excessive sleepiness is present in the general population. In a population-based

healthy adult sample of Southeastern Michigan drivers [4], recruited subjects were
divided into groups based on average multiple sleep latency testing (MSLT) latency
as follows: severe (0.0 to < or = 5 min; 11% of the sample), moderate (5–10 min;
33%); and alert (>10 min; 56%). Prior 10-year state-documented rates for state
motor vehicle reports were significantly different among groups (Fig. 7.1a). When
the victim was the only occupant of the car, subjects with highest sleepiness had the
greatest crash rate compared with alert individuals (p = 0.022). In the reporting of a
severe injury, a higher prevalence (p = 0.03) was found in those who were excessively
sleepy (4.3%) than in those who were moderately sleepy (0.5%) or alert (0.6%)
(Fig. 7.1b). Thus, objectively “excessively” sleepy but healthy people appear to
have had more crashes, and more severe crashes, in their driving history.
7 Assessments of Driving Risk in Sleep Apnea 131

In those presenting for medical assessment, self-reported sleepiness is widespread.

In a cross-sectional primary care survey of more than 6,000 waiting room patients,
24% reported sleepiness and 14% reported drowsy driving. There were regional
differences (Europe vs. United States, and among various practices in the United
States), and men (18.3%) reported drowsy driving more than women (9.8%). In this
group, 34% met a risk profile for sleep apnea [5]. In a study in a Cleveland VA popu-
lation using a similar methodology, 26% reported sleepiness and this correlated
with Epworth Sleepiness Scale (ESS). While the mean ESS score (normal <11) was
8, over 40% had a score >11 and 4.6% had a score >17. Of these respondents, 47%
met high-risk criteria for sleep apnea, 41% for insomnia, 19% for restless leg syndrome,
and 4.7% for narcolepsy [6]. In another VA population using a similar methodology
in Puerto Rico, 34% met high-risk criteria for sleep apnea, 53% for insomnia, 13%
for symptoms suggestive of narcolepsy, and 13% for those suggestive of restless leg
syndrome [3]. While it is unlikely that all of those with self-reports of symptoms
will have disease, such individuals could be referred to pulmonary physicians or
others with sleep expertise to be evaluated not only for a suspected disorder but also
for management of excessive sleepiness.
There are some 40 articles on the subject “sleep apnea” as a categorical element
for drowsy driving crashes. Two meta-analyses [7, 8] found that the majority of
articles reported statistically significant, two- to three-fold risk between a diagnosis
of sleep apnea and prior crash. For commercial drivers, only one of three studies
found an increased crash rate, and this association was weaker (OR 1.3). The evidence
was inconclusive regarding whether the risk was proportional to severity of the
sleep apnea or to subjective daytime sleepiness. Treatment of sleep apnea appeared
to reduce risk in a similar analysis of the exiting literature [9]. However, not all
patients with sleep apnea have excessive daytime sleepiness [10] nor have experienced
an automobile crash [11].
This article reviews publications from the past and present body of knowledge
regarding pulmonary physician assessment and responsibilities for dominant symp-
toms of sleepiness and drowsiness. The diagnostic reasoning, clinical testing, and
patient management issues for sleep disorders are described in greater detail in other
chapters of this book. At issue here are the assessment and mitigation of drowsy
driving and related accidents, injuries, and possible death. This is not a “how to”
report but an annotated description of the landscape of decision-making and interactions
that the pulmonary physician will have in this context of driving risk assessments
(Fig. 7.2).

Factors in Driving Risk

Driving a motor vehicle is a complex task that engages several physical and psycho-
logical skills; it is estimated that over a minute the driver in an urban setting makes
20–40 cognitive decisions a minute [12]. Driving certainly involves skills beyond
that affected by sleepiness, including neurocognitive deficits associated with the
132 K.P. Strohl

La icy

Dr and
w
l

ive Ad
. a l Po

r R he
ion ra
nd

es ren
lat de

po ce
gu Fe
Interactions

ns
Re e or
Beyond that of

ibi
lity
t

Clinical Assessment
Sta

or Medical Necessity

Physician: Role and Responsibility

Fig. 7.2 Interactions and parties to an assessment of driving risk. This graph depicts the relationships
inherent in an assessment of driving risk and shows that the actions of the physician are performed in
a broad context of interactions with society, in particular state and federal rules and regulations for
driving privileges, and with the patient or client as an individual or as a member of society

co-morbidities of sleep apnea, such as hypertension, stroke, aging, medications for

other chronic diseases, etc. [2, 12, 13]. Indeed a recent large study of medical
outpatients concluded that in the absence of sleep apnea or other known sleep
disorders, shift work and narcolepsy, independent predictors of excessive waketime
sleepiness were ulcers OR = 2.21 (95% CI = 1.35–3.61) followed by migraines
OR = 1.36 (95% CI = 1.08–1.72), and depression OR = 1.46 (95% CI = 1.16–1.83)
after controlling for other conditions, age, gender, time in bed, caffeine, smoking,
and alcohol use [14].
Obstructive sleep apnea (OSA) is associated with more crashes [8] and treatment
with CPAP reduces crashes in patients with OSA by ~70% [9]. This finding is con-
sidered plausible given that driving simulator testing and reaction times consistently
improve in those who are issued CPAP, especially in those who use it regularly
(>4 h a night for >50–70% of nights). However, treatment may also result in greater
alertness and vigilance while driving, despite little change in sleepiness [15] or less
sleepiness but unchanged residual cognitive problems relating to planning and judg-
ment [16]. One study used a driving simulator to determine how rapidly a person
could respond to therapy and reported improvements in 2 days, but more benefit
may accrue over several weeks [17]; however, it should be noted that poor performance
on a simulator does not regularly predict a motor vehicle crash or accident [18].
An appropriate question is whether treatment of sleep apnea reduces risk to that
of the general population [11]. Findley et al. was the first study to confirm with traffic
records that patients being treated with nasal CPAP for sleep apnea had fewer auto-
mobile crashes and that the 2-year crash risk, while initially several fold higher,
became that of the general population of the state of Colorado [19]. This study involved
7 Assessments of Driving Risk in Sleep Apnea 133

50 patients with sleep apnea symptoms and AHI >15. While selection bias and
regional specificity of the study limited broad conclusions, subsequent studies have
confirmed this assessment [20]. Risk is reduced by recognition and treatment,
perhaps even by an intent-to-treat [9].

The Interactive Responsibilities of a Driving Assessment

Pulmonary physicians are expected to diagnose, treat, and assess illness, in general,
and, with discovery of excessive or problematic waketime sleepiness, to recognize
the potential impact of this symptom has on health and behavior. A particular
element that would obligate the physician to intervene would be the presence of
severe waketime sleepiness and a history of a previous motor vehicle accident or
“near-miss” events that suspicion suggests is due to excessive sleepiness. This infor-
mation alone is sufficient to immediately warn the patient of the potential risk of
driving until effective therapy is instituted, and provide additional counseling to the
family members. Not all patients suspected of having sleep apnea will present with
a high level of sleepiness risk. Steps to reduce risk can be instituted awaiting diagnosis
and treatment and a plan to assess the patient’s response with a goal of reducing risk
to that of the general population.
When the physician informs the patient of the diagnosis and makes cautionary
recommendations, the legal status of the patient as a motor vehicle operator is
irrevocably changed. In the event that the patient thereafter has a traffic accident, the
patient no longer can avoid civil and criminal liability by claiming that his falling
asleep was sudden or unexpected [21]. For this reason alone, the physician should
document his warning in writing, noting the reason for concern, or any recommen-
dations specific to the individual patient [1]. Such an approach will reinforce the
seriousness of the warning [2].
The pulmonary physician also is in a position to help the patient to restore his/her
driving privileges whenever there is reasonable indication that the causes for excessive
waketime sleepiness have been addressed including effective treatment. A restriction
based on sleep apnea should not be regarded as permanent, in contrast to a diagnosis
of narcolepsy.
Reporting responsibilities of the physicians will differ from one state to another,
and according to the circumstances of a referral. Whether a report on a particular
patient should be filed will depend on the state laws, policy, and regulations. Many
state laws appear to allow room for a physician to report a patient if the physician
believes the patient presents a current risk; but other state laws may obligate the
physician to report based on diagnosis or symptoms alone. The physician is obligated
to adhere to the requirements of the law in the specific state in which he or she
practices, even if those laws do not reflect sound public policy or medical evidence.
In those instances in which the licensing agency has been notified about a
patient’s condition (by the patient, physician, or anyone else), it is appropriate for
the agency to consult a specialist with respect to the patient’s ability to operate a
134 K.P. Strohl

motor vehicle. However, in the opinion of an expert panel convened by the American
Thoracic Society, the physician is in no position to certify the patient’s ability (fitness)
to operate any motorized vehicle given the absence of training in motor vehicle
licensure [1]. It is the DMV that has the legislated mandate to do this. However, the
physician can comment on the nature and facts of the diagnosis, the facts concerning
treatment, and the extent of treatment effectiveness.
There are inherent problems in the event that a sleep study or measures of sleepi-
ness or performance are administratively requested to assess driving fitness. The first
is that test outcomes are not closely linked to foreseeable driving risk. Even those
assessments with MSLT in population noted in the Introduction were associated
with retrospective crashes, and the differences between the highest and the lowest
degrees of sleepiness may not necessarily drive policies in a democratic society or
across states. The second is that there are rather loose correlation among AHI
numbers, treatment effects, and drowsy driving because sleepiness is multifactorial,
affected by sleep length, shift work, and medications even if the immediate medical
condition, i.e., sleep apnea, is successfully treated. In one study, more than two-thirds
of patients with sleep apnea had no reported crashes during a 5-year period [22].
Weight loss, fitness, avoidance of allergen exposure that produces allergic rhinitis,
discontinuation of alcohol or another sedating medication, and more sleep opportu-
nity and sleep time length can reduce sleepiness even if apnea number is not reduced.
A third factor is that foreseen risk is affected by diagnosis even in the absence of
institution of direct therapy. The patient and/or family will often institute reductions
in risk exposure if discussed with the family [1].
Any authority requesting documentation of a clinical encounter should include a
release indicating patient consent. It should also be noted in the release of data from
polysomnography reports or titration results or trends in ESS values that these
“snapshots” have not been shown to have predictive value in the prevention of an
accident in an individual patient. As treatment vs. no treatment seems to be a key
component, one could consider measures of CPAP compliance; but if a patient is
treated by another mode of therapy, such adherence data are not available.

Potential for Liability Risk for Pulmonary Physicians

Here the issue is how driving risk assessments are seen in the context of physician
work. It is important to recognize that pulmonary physicians would be considered
as being trained to assess and manage sleep apnea, in contrast to a primary care
practitioner, or other nonsleep specialists. The expertise extends to a skill set in
symptom assessment, including those of excessive sleepiness and the potential for
drowsy driving present in some patients with sleep apnea. Therefore, a pulmonary
physician would be expected to assess the degree of sleepiness and know what to do
to mitigate risk.
As noted above the section on Factors in Driving Risk, identification of excessive
driving risk by a point-of-service clinical assessment for sleep apnea is difficult.
AHI values alone are not generally useful. In George et al. [23] the rate of prior
7 Assessments of Driving Risk in Sleep Apnea 135

accidents/year, was highest in those with the highest AHI, >40/h, but many had not
had an accident. Similarly, Horstmann et al. [24] found an increased motor vehicle
accident rate only in patients with more severe SAS (AHI > 34). These were studies
performed without controls. In the only follow-up case–control study of those with
crashes, Kingshott et al. [25] reported that OSA drivers in crashes demonstrated
significantly more driver sleepiness, slower reaction times and a trend for greater
objective sleepiness compared with well-matched controls; however, controls
showed moderate levels of unrecognized mild (5–15 AHI) sleep apnea as well.
The implication was that sleep apnea was common in both controls and crash drivers
and that the difference was in some other neurocognitive domain. However, there
are no clinical methods or guidelines for routine neurocognitive testing in a pulmonary
practitioner’s office, so any approach using such tests is currently impractical.
Therefore, the assessment will need to be at the point-of-service.
In the course of an evaluation, the patient/client and the physician are expected
to act responsibly. While the physician is often trained to treat historical reports with
some skepticism, there is an expectation that a patient will report to the best of their
ability the symptoms and signs of disease, heed advice, and comply with therapy.
Hence, it is important to inform the patient of the manner and purpose of the assessment
and discuss the conclusions based upon the evidence. This is important especially if
the visit is a 1-time assessment. Once informed of being at high risk for drowsy
driving by a physician, failure by the licensed driver to take seriously suggested
measures to reduce driving risk can carry consequences beyond the obvious threat
to personal health. Such a failure to act can include a voidance of insurance and/or
civil and criminal liabilities [21, 26–28].
The manner in which one informs the patient that he/she is at high risk is not
established either in terms of customary practice nor for in the course of an adminis-
trative referral. The 1994 document from the American Thoracic Society suggested
a form to be signed by a patient that the presentation was consistent with excessive
waketime sleepiness and a high risk for drowsy driving, that this was discussed, and
that in the opinion of the physician it was reasonable to reduce driving until such a
condition was treated or sleepiness was reduced [1]. This approach has not been
widely adopted, and in practice is difficult to institute as it carries no impact if the
document is not signed. It is however appropriate to note in the office documentation
that the topic was discussed on that day and what if any specific steps were suggested
to reduce the high risk for drowsy driving. In the short term, such interventions as
noted above could include advice about longer sleep opportunity, improved sleep
hygiene, etc. In the long term, there might be more diagnostic testing or treatment.
Finally, in the event of a referral from a regulatory agency or its representative,
including a commercial medical examiner, the visit is not based on medical neces-
sity. In such instances, the cost of a physician visit and any testing may be denied.
In addition, medical malpractice may not cover this interaction as it does not reflect
a clinical problem or solution. In this instance, there may be more incentive for the
driver to downplay symptoms of sleepiness or even of disease, not only to be eligible
to drive but also to reduce expenses of testing. Hence, the circumstance of the referral
is important to document the medical as well as administrative issues with clarity
and attention to the consequences to the patient/client.
136 K.P. Strohl

Societal Implications

Sleep apnea is considered by many to be a “red flag” for reduced fitness to drive, but it
should be pointed out that many persons with sleep apnea would still be considered
safe to continue driving. The subsets which appear to present an elevated risk are
those with excessive waketime sleepiness, rather than those categorically identified
by either a diagnosis or a threshold number of events.
It may be potentially appropriate for commercial driver assessments to use the
number of sleep apnea events or even a composite risk of associated traits (obesity,
snoring, gender, and/or age) as triggers for concern; however, even this “screening”
as its own problems given the prevalence of an AHI >5 in the population and the
intersection of common elements (sleepiness caused by sleep restriction, obesity,
medications for disease that produce drowsiness, snoring, etc.). For instance, BMI
was recently proposed by a panel of medical experts to use BMI as an objective and
identifiable risk for sleep apnea in commercial driver assessments. There is one study
utilizing portable monitoring which identified only a BMI threshold of >30 as a risk
factor (twofold higher accident rate per mile) for commercial drivers [29]. Whether
a threshold BMI value is a viable option for routine testing in the absence of evaluation
for ancillary signs and symptoms remains to be determined. In Ohio, 33% of the
population of 20 million over the age of 16 years (potential noncommercial drivers)
have a BMI >30, and the proportion of those seeking commercial licenses (150,000/
year in Ohio alone) who have a BMI >30 is even higher. Routine testing for BMI
alone is impractical. Furthermore, obesity has a socioeconomic dimension so that
any assessment for risk based on BMI would have disproportionate, and potentially
burdensome, effects on minority populations [30]. Such approaches would lead to
unnecessary testing and added cost, and probably be unpopular.

Lessons from the Alcohol Literature

Up to this point, we have considered the case for assessment and management of
excessive waketime sleepiness because of personal and societal risk. The data generally
show that excessive sleepiness degrades driving skills and that some patients with
sleep apnea will present with excessive waketime sleepiness. Finally, treatment of sleep
apnea will reduce sleepiness and may reduce risk of drowsy driving to that of the
general population. Thus, one concludes that excessive sleepiness is a substantial
public health risk and steps need to be taken at regulatory and liability levels to
reduce this risk. At this point, however, one should consider how a physician is asked
to screen for another well-recognized risk factor for car crashes, namely alcohol.
Alcohol and sleepiness are similar in terms of effects that lead to “impairment,”
the condition of being unable to perform as a consequence of physical or mental
unfitness [27]. Both produce cognitive and eye–hand slowing of responses, limits
decision skills, lead to increased errors of commission and omission, and declines
7 Assessments of Driving Risk in Sleep Apnea 137

Table 7.1 Comparison of effects on neurocognitive functions

Function Alcohol Sleepiness
Cognitive speed Slowed Slowed
Decision skills Become limited Become limited
Errors (commission and omission) Increased Increased
Eye–hand coordination Slowing and errors Slowing and errors
Divided task Impaired Impaired
Dose–response Yes Yes
Eye-hand coordination performance

1.04

1.02

Blood Alcohol %
1
0.05
.98

.96

.94 0.10

.92
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29
Hours Awake

Fig. 7.3 Relative impairments of sleep deprivation and alcohol. This figure depicts the results in
an eye–hand coordination task expressed as a percent of baseline over a 29-h period of sleep depri-
vation. Shown on the right vertical axis is the impairment at a given alcohol level in the same task.
The data are adapted from Arendt et al. [32]

in divided-attention task (Table 7.1) [12, 31]. Both are accompanied by a lack of
situational awareness of the degree of impairment, and both show dose-related
effects, and there is an equivalency of impairment (Fig. 7.3) [32]. These adverse
effects are reversed, the former by metabolism and the latter by adequate sleep or
circadian rhythm. The effects of a combination of alcohol and sleepiness are more
than additive [33]. Thus, in both conditions the physiology and pathophysiology are
fairly well understood.
Driving while impaired by alcohol accounts for 32% of all traffic-related deaths [34].
Individuals with a first conviction for drunk driving have a high rate of recidivism,
and about 30% of those involved in alcohol-related crashes have a prior arrest or
conviction for the same offense [35]. Countermeasures at a public health level are
directed at multiple levels – point-of-arrest sanctions, as well as assessments when
treatment for a crash-related injury.
Laws regarding detection, reporting, and convictions for drunk driving exist in all
states and territories of the United States [36]. There are efforts to improve technology
138 K.P. Strohl

to detect alcohol levels while driving [37]. Moreover, there is a major push to
publicize the risk and to educate the public on the dangers of drunk driving and the
consequences of being discovered impaired by alcohol. The cost-effectiveness of
these efforts are considered to be “modest” [38]. In this literature the emphasis is on
detection and intervention at the first event, and prevention is aimed at general
education, publicity, random testing, and stiff legal penalties. There is no general
effort directed at physicians to predict and preempt drunk driving before it happens,
but rather an effort to have physicians using historical evidence [35] or nurses in
emergency room settings [39] intervene to reduce the next instance.
Legal remedies for drowsy driving are nonuniform across states. Prompted by an
absence of a law to convict a driver after a death of a second party by his falling asleep
at the wheel after >30 h of continuous wakefulness, New Jersey statute NJ H. R. 968,
2003 makes it an automatic felony charge if one has an accident after 24 h of sustained
wakefulness [40]. Some 11 other states have had similar legislation drafted at a
committee level and there has been an effort to make this a national regulation.
Using an analogy to alcohol risk to address excessive sleepiness, however, has
several other problems. First, an objective, point-of-service measure for sleepiness
in a driving crash is lacking. This makes it difficult to confirm or quantify for inter-
vention. Second, the public is not prepared educationally about dangers of sleepiness
in general and driving impairment caused by excessiveness sleepiness in particular.
Admittedly there are efforts to publicize drowsy driving but these are directed at
commercial sector, e.g., Parents against Tired Truckers and the Truck Safety
Coalition, where the driving risk may actually be lower that for noncommercial
drivers. Attention paid to the connections between extended hours of service and
sleepiness in housestaff, but these are more often seen as special cases applicable to
medical errors rather than drowsy driving and risk to the public. Third, the details of
legal remedy will be difficult to implement across states. Alcohol limits and defini-
tions of impairment are made at a state level. It took many years after the impairments
of alcohol were well described to accomplish these legal standards state-by-state,
and full implementation some 25 years ago was accomplished by tying acceptance
of highway funds to the implementation of laws to regulate drunk driving [36].
Such a proposal to tie state efforts to reduce drowsy driving to availability of federal
funds may not yet have sufficient political or social import compared to other issues.
Thus, not only is it difficult to identify and quantify drowsy driving, but the groundwork
for acceptance of drowsy driving as a public risk as impairment and at the same
plane as drunk driving is lacking.
At the present time, an informed general public about the effects of sleepiness
and the effectiveness of sleep as a countermeasure is of highest priority prevention
of motor vehicle crashes, unintended injury, and/or unintended death from excessive
waketime sleepiness. Such an effort is necessary to implement formal medical
assessments or any punitive measures designed to reduce risk. Information on
drowsy driving should be incorporated into educational and evaluation materials for
licensing and operation of noncommercial vehicles.
7 Assessments of Driving Risk in Sleep Apnea 139

Principles in Assessment of Risk by the Pulmonary Physician

Under general principles of malpractice liability, physicians are obligated to adhere

to the prevailing standard of care [2]. Pulmonary specialists are expected to be aware
of the presentations and complications of excessive sleepiness, of which sleep apnea
is a common cause.
At the present time, driving risk is considered elevated by the presence of moderate
and severe sleepiness, as based upon historic information from the patient or an
informed observer, of which the strongest evidence is a history of a previous motor
vehicle crash, and response to therapy is also judged similarly [1]. There is no reliable
objective test that is predictive of increased driving risk or that would indicate that,
after treatment, driving risk has been reduced to an acceptable level. Asking direct
questions of driving risk in the context of a clinical examination is subject to driver
bias and physician interpretation of the history. Of course, retrospection by the
patient or family after treatment may have identified higher potential risk before
treatment. These general observations make it difficult to assign to an individual
risk before treatment, and are more useful in supporting continued treatment and
management of the primary cause, be it sleep apnea or sleep restriction or voluntary
cessation of driving.
Triggers for direct questioning of the presence of active sleepiness might be
either a high (>17/24) ESS score, a personal report of excessive sleepiness interfer-
ing with activities of daily living, or family report of drowsy driving. In the opinion
of the committee, a time span limited to “recent times” is appropriate, rather than
lifetime exposure. Subjective rating scales, such as the ESS, can be used in clinical
and epidemiological settings [11]. The eight questions of the ESS ask about the
tendency to fall asleep in recent times, but these circumstances are passive in nature.
They do not ask for instances of sleep attacks that occur while a person is trying to
do something, i.e., active sleepiness. Also, their usefulness is limited; for instance,
the ESS cannot be used to demonstrate or exclude sleepiness as it is measured by
objectively [41]. Recently, a single simplified question was piloted against ESS and
objective testing and found to have some internal validity [42]. This question “Please
measure your sleepiness on a typical day” was rated from 0 = none to 10 = highest.
Scores < or = 2 or > or = 9 reliably predict normal or abnormal ESS scores, respectively.
Since the ESS is not commonly used in nonsleep specialized practices, this simpli-
fied screening question was proposed as a useful screening tool for patients with
disorders of sleepiness.
The American Thoracic Society committee report identified that the common
elements for assessment are: notation of initial severity in clinical terms; assessment
of sleepiness by ESS and initially direct questions about drowsy driving; time estimate
for or of diagnosis and time estimate for or of initiation of therapy; type of therapy
including behavioral interventions, as appropriate; specific notation of the start of
therapy by Positive Airway Pressure or other instituted therapy; documentation
of adherence to Positive Airway Pressure Therapy or, as appropriate, the response
140 K.P. Strohl

to another therapy, as appropriate; and reassessment of drowsy driving, if the patient

was at any prior point in time at high risk.
A point of service assessment often cannot be dependent on outside information
to be obtained later. While it is advocated that family members or others provide
additional insight about sleep and sleepiness at the time of the initial evaluation, it
is not required that the physician wait to make an assessment if such information is
not available at the time of risk assessment. Setting aside issues of patient release
and of physician knowledge of how to interpret such results, obtaining an official
driving record might not arrive in a timely manner, given the need for proper release
of information and bureaucratic inertia. Waiting for PSG results is not an attractive
alternative as knowing the AHI and then assigning risk puts the patient into double
jeopardy; if the patient was not deemed a risk before a diagnostic sleep study, then
how could he/she be one after the study. Likewise, the assessment of risk after initiation
of therapy should be performed in those deemed at highest risk before initiation of
therapy. Treatment, even intent-to-treat, may reduce risk.

Summary of Keypoints

• Sleepiness, also termed drowsiness, is defined by a set of neurocognitive behaviors

within the state of wakefulness.
• A direct, functional outcome of excessive sleepiness is impaired driving perfor-
mance and increased risk for drowsy driving and motor vehicle crashes, including
fatalities.
• In regard to sleep apnea, whether crash risk is proportional to apnea severity or
to subjective daytime sleepiness is at present unknown, as there are multiple
other causes for sleepiness and inattention.
• While in small studies treatment of sleep apnea appeared to reduce risk, not all
patients with sleep apnea have excessive daytime sleepiness nor have experienced
an automobile crash.
• Physician assessments at the point of service would have a purpose to mitigate
drowsy driving; however, the advice here is anecdotal.
• This chapter is an annotated report of the landscape of decision-making that the
pulmonary physician will encounter in the context of driving risk assessments.

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Chapter 8
Nasal Continuous Positive Airway Pressure
(CPAP) Treatment

Srinivas Bhadriraju and Nancy Collop

Keywords Continuous positive airway pressure • CVPAP titration • Adherence

• Cognitive behavior therapy • Daytime hypersomnia • Motor vehicle accidents

Mechanisms

Continuous positive airway pressure (CPAP) remains the treatment of choice for
patients with obstructive sleep apnea (OSA). The mechanism by which CPAP
maintains the patency of the upper airway in patients with OSA is by acting as a
pneumatic splint. The authors of the paper introducing CPAP as a treatment modality
for OSA suggested this mechanism in 1981 [1]. Subsequent research explored other
mechanisms and confirmed this notion and showed that CPAP can increase upper
airway volume by ~20% [2]. CPAP does not stimulate upper airway dilator muscle
activity as shown by electromyography (EMG) of alae nase or genioglossus [3].
In another study seeking to understand the airway changes induced by CPAP, the
authors reported increase in increased lateral airway dimensions rather than antero-
posterior dimensions due to a reduction in pharyngeal wall thickness. Soft palate
and tongue did not show significant changes [4]. Finally, CPAP also increases lung
volume, although this effect alone is not adequate to treat OSA due to the upper
airway obstruction [5].
The optimal pressure required to eliminate OSA is inversely related to increasing
age and increasing lung volumes [6]. Room air is pressurized in the device and
delivered through an interface to the patient’s airway. Intermittent collapse of the

S. Bhadriraju
Pulmonary/Sleep Medicine, Emory University School of Medicine, Atlanta, GA, USA
N. Collop (*)
Emory Sleep Center, Emory University, Atlanta, GA, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 143
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_8,
© Springer Science+Business Media, LLC 2012
144 S. Bhadriraju and N. Collop

pharyngeal airway is a key component in the pathophysiology of OSA. The patency

of the pharyngeal airway depends upon the balance between the intraluminal and
extraluminal forces that act in opposite directions. We can understand this concept
by the Starling resistor model. Based on this model, critical pharyngeal pressure
(Pcrit) is negative in normal individuals during sleep, while it is positive in patients
with pharyngeal airway collapse [7–9]. Pcrit is influenced by physical factors like
peripharyngeal pressure [10] as well as lung volumes, and varies inversely with end-
expiratory lung volume [11]. This model provides a conceptual platform for the
basis of CPAP treatment. The objective of a CPAP titration study is to gradually
increase the pressure applied at the nose until there is resolution of pharyngeal airway
collapse. This occurs when the pressure applied at the nose exceeds the Pcrit.

Beneficial Effects

CPAP has shown to be beneficial based on several outcome measures in patients

with OSA. Examples of these are outlined below.

Excessive Daytime Sleepiness

Excessive daytime sleepiness (EDS) is a major symptom of patients with OSA.

Improvement in EDS would be a visible testimonial of the effectiveness of CPAP in
the treatment of OSA from the patient’s perspective. Several studies have addressed
the beneficial effect of CPAP on EDS in patients with OSA. Yamamoto et al. studied
47 patients with OSA and concluded that CPAP improves EDS in patients with
OSA [12]. A Cochrane review of 36 trials involving 1,718 people concluded that
compared with control, CPAP therapy demonstrated significant improvements in
both objective and subjective sleepiness measures [13]. Interestingly a study of 55
patients with severe OSA [apnea hypopnea index (AHI) of greater than 30 events/h]
and no daytime sleepiness showed that CPAP was not effective in improving objec-
tive measures of sleepiness, cognitive function, or blood pressure [14]. This finding
highlights the importance of viewing the diagnosis of OSA, as not limited to a
number, i.e., AHI, especially when there is no associated daytime sleepiness. AHI
can vary from night to night, it is inversely related to the length of each individual
apnea or hyponea, and hence a lower AHI or high AHI gains significance only when
associated with clinical consequences which includes EDS.

Blood Pressure

Systemic hypertension is perhaps the most studied and well-documented consequence

of OSA. Several mechanisms, including excessive sympathetic discharge, vascular
8 Nasal Continuous Positive Airway Pressure (CPAP) Treatment 145

inflammation, oxidative stress and endothelial dysfunction may be contributing to

the development of systemic hypertension in patients with OSA. It then makes
mechanistic sense that CPAP treatment of OSA may improve blood pressure control
by reversing these abnormalities. Several studies evaluated the effectiveness of
CPAP treatment in BP control over the last 2 decades. A meta-analysis of 12
randomized control trials which included 572 patients showed that CPAP treatment
was effective in reducing the mean 24-h ambulatory blood pressure [15]. Similarly,
Jaimcharitam et al. demonstrated that CPAP treatment improves blood pressure
even in mild OSA patients [16].

Pulmonary Hypertension

OSA is considered in class III of World Health Organization (WHO) classification

for pulmonary hypertension (PH) [17]. The mechanism by which OSA likely causes
increases in pulmonary artery pressures is through hypoxemia. It then follows that
treatment of OSA using CPAP may improve the PH by eliminating the associated
hypoxemia. In a randomized crossover trial of 23 middle-aged patients with OSA,
echocardiographic measurements of pulmonary artery systolic pressure and urinary
catecholamine levels were higher in OSA patients than in controls, and improved
with CPAP treatment [18]. These findings are in agreement with earlier studies that
showed improvement in pulmonary arterial pressure as well as hypoxic pulmonary
vascular reactivity after CPAP treatment in patients who had OSA but were other-
wise healthy [19].

Heart Failure

The benefits of CPAP in patients with heart failure may extend beyond the effect of
increased lung volume. In a prospective study, 24 patients with OSA and coexisting
congestive heart failure were randomly assigned CPAP or medical treatment alone
[20]. The CPAP group showed improved blood pressure, heart rate associated with
improved OSA. The left ventricular ejection fraction improved from 25.0 ± 2.8 to
33.8 ± 2.4% (P < 0.001). In another multicenter study, 60 patients with chronic heart
failure showed improved cardiac output in 3 months after CPAP treatment. The
improvement was significant in patients with LVEF greater than 30% [21].

Cardiac Arrhythmias

Cardiac arrhythmias, including atrial fibrillation (AF), have been reported in patients
with OSA. In a landmark study by Kanagala et al., patients with AF and OSA who
146 S. Bhadriraju and N. Collop

were about to undergo treatment with cardioversion were studied prospectively for
recurrence of AF after treatment of OSA [22]. Rates of recurrence of AF were
compared among three groups: treated OSA, untreated OSA, and a control group.
Recurrence of AF at 12 months in the untreated OSA group (n = 27) was 82%; in the
treated OSA group was 42% (n = 12, P = 0.013); and in the control patients 53% (n = 79,
P = 0.009). The nocturnal fall in oxygen saturation was greater (P = 0.034) in those who
had recurrence of AF (n = 20) than in those without recurrence (n = 5). CPAP treatment
may reduce or resolve the arrhythmias by resolving the obstruction and related
consequences. However, large randomized studies are lacking in this regard.

Neurocognitive Function

In a randomized control trial, 46 patients with OSA were randomized to receive

supplemental oxygen, sham CPAP, or therapeutic CPAP [23]. A battery of tests of
neurocognitive function was performed. A 2-week trial of therapeutic CPAP improved
speed of information processing, vigilance, and sustained attention and alertness.
In a separate study, a subset of patients with Alzheimer’s disease was shown to expe-
rience improvement in neurocognitive function and memory [24]. However, all the
outcomes are not necessarily positive. In a prospective study, 37 patients with severe
OSA were compared with normal controls in terms of neuropsychological measures
of complex attention, executive function, and psychomotor speed. The OSA group
fared worse when compared to the control group even after CPAP treatment suggesting
that some cognitive deficits may be resistant to treatment [25]. At this time, a multi-
center prospective study sponsored by the National Heart Lung and Blood Institute
(NHLBI) called Apnea Positive Pressure Longterm Efficacy Study (A.P.P.L.E.S.) is
underway. This study focuses on the effectiveness of CPAP on memory, learning,
sleepiness, mood, and quality of life. It is hoped that the results of this study will shed
further light on the effect of CPAP on neurocognitive function.

Glucose Metabolism

OSA may affect glucose metabolism via the pathway of intermittent hypoxia.
Insulin sensitivity is the amount of insulin required to maintain normoglycemia
when a subject is given a glucose challenge. Impaired insulin sensitivity or insulin
resistance suggests predisposition to diabetes or may be part of the metabolic
syndrome. At least four studies of almost 900 type 2 diabetic patients suggest a
prevalence of OSA in that population of 73% [26–29]. Such observations raised
interest in the potential relationship between OSA and diabetes, and consequently
the possibility of improvement or resolution of diabetes with treatment of coexisting
OSA. Studies to date examining the effects of CPAP on glucose control show
8 Nasal Continuous Positive Airway Pressure (CPAP) Treatment 147

conflicting results. Babu et al. investigated obese, diabetic patients (n = 25) and
showed that after 3 months of CPAP there was improvement in HgbA1c and post-
prandial glucose levels which were better in those using CPAP more regularly [30].
Improvements in nighttime glucose levels during one night and 5 weeks of CPAP
use have been shown in two other studies [31, 32]. Three other studies, however, did
not show significant changes in HbA1c levels, but two of them did document some
improvement in insulin sensitivity [33–35].

Motor Vehicle Accidents

OSA is associated with increased risk for motor vehicle accidents. Excessive sleepiness
and impaired reflexes due to sleep deprivation may play a role in the increased risk.
In a study of 80 patients with OSA and 80 control subjects, patients with OSAS had
a 2.6-times higher risk of suffering a motor vehicle accident than controls (rate ratio,
RR = 2.57; 95% confidence interval, CI = 1.30–5.05) [36]. The rate of accidents was
reduced more than 50% in patients with OSA (RR = 0.41; 95% CI = 0.21–0.79),
although this also occurred in controls in this study (RR = 0.49; 95% CI = 0.17–1.40).
Another study has showed that the increased risk for motor vehicle accidents was
reduced after 3 months of CPAP treatment [37].

Adverse Effects

Patients using CPAP will complain of nasal dryness, rhinorrhea, and less commonly,
epistaxis. Flow-related side effects may include chest discomfort, aerophagia and
feeling of “smothering” due to difficulty exhaling against the pressure. The mask
may cause skin allergies or facial abrasions. Conjunctivitis due to the airflow can
occur. These adverse affects can range from minor inconvenience to significant
interference with therapy and result in nonadherence. Regular clinical follow-up
with careful attention to the adverse effects is important in ongoing treatment of
OSA utilizing CPAP.

Setting Up CPAP

When initiating CPAP, there are numerous options available. The current standard
is to perform a single overnight polysomnogram while the patient is monitored so
the attendant can increase CPAP levels to progressively eliminate disordered breathing
events. However, split night studies, autotitrating PAP devices, and other empiric
methods of initiating CPAP are also available.
148 S. Bhadriraju and N. Collop

Titration

The current gold standard is a full-night-monitored CPAP titration in a sleep laboratory.

Patients are set up to undergo polysomnogram. The CPAP is generally initiated at a
setting of 5 cm of water after appropriate measurement of the facial area and mask
fit. The CPAP setting is gradually titrated in increments of 1–2 cm of water at a time.
The titration is guided by resolution of snoring, resolution or substantial improvement
in airflow pattern and apneas and hyponeas as well as tolerance by the patient.
Central apneas are sometimes seen with CPAP titration. These are usually self-limited.
An ideal titration should include adequate time at each setting and also include
supine and REM sleep. OSA tends to be more severe in the supine position and
during REM sleep and achieving a pressure setting that is adequate in the supine
and during REM sleep is an important consideration. Some studies are “split,” i.e.,
in a patient with severe OSA that meets the preset criteria for severity, the definition
of which will vary among sleep laboratories, the CPAP titration is initiated after at
least 2 h of a diagnostic study.

Auto Titration

With increasing demand for services and difficulties associated with access to sleep
laboratories and costs, there has been interest in performing out of sleep center
titrations utilizing autotitrating PAP machines. In selected patient groups without
serious comorbidities, these devices may be adequate. Autotitrating PAP (APAP)
has been advocated as an alternative to traditional CPAP titration. The laboratory-
based titration may be limited by night-to-night variability in pressure requirement,
the inconvenience of laboratory environment, costly nature of sleep studies, and the
time lag between diagnosis of OSA and institution of therapy. A meta-analysis of
nine randomized controlled trials involving 292 patients showed that while APAP
reduced the mean pressure by 2.2 cmH2O, it was equivalent but not superior to
traditional titration in terms of adherence, ability to eliminate respiratory events and
EDS as measured by Epworth sleepiness scale scores [38]. Two groups of patients
in whom autotitrating PAP may not be appropriate include patients with serious
cardiopulmonary illness and patients with obesity hypoventilation syndrome. The APAP
machines algorithm will increase the pressure settings within a preset range based
on flow limitation. The above-mentioned patients may have persistent hypoxemia
which may not be detected by the APAP machines. Additionally, mouth breathing
or leaks may be recognized as flow limitation resulting in inappropriate increase in
pressure which may exacerbate the leak resulting in a vicious cycle. The current
recommendations by the American Academy of Sleep Medicine Taskforce practice
parameters are reproduced in Table 8.1 [39]. At this time, APAP cannot be recom-
mended as first-line therapy in all patients with OSA.
8 Nasal Continuous Positive Airway Pressure (CPAP) Treatment 149

Table 8.1 AASM recommendations for APAP use [39]

APAP devices are not recommended to diagnose OSA
Patients with congestive heart failure, patients with significant lung disease such as chronic
obstructive pulmonary disease; patients expected to have nocturnal arterial oxyhemoglobin
desaturation due to conditions other than OSA (e.g., obesity hypoventilation syndrome);
patients who do not snore (either naturally or as a result of palate surgery); and patients
who have central sleep apnea syndromes are not currently candidates for APAP titration
or treatment
APAP devices are not currently recommended for split-night titration
Certain APAP devices may be used during attended titration with polysomnography to identify
single pressure for use with standard CPAP for treatment of moderate to severe OSA
Certain APAP devices may be initiated and used in the self-adjusting mode for unattended
treatment of patients with moderate to severe OSA without significant comorbidities (CHF,
COPD, central sleep apnea syndromes, or hypoventilation syndromes)
Certain APAP devices may be used in an unattended way to determine a fixed CPAP treatment
pressure for patients with moderate to severe OSA without significant comorbidities (CHF,
COPD, central sleep apnea syndromes, or hypoventilation syndromes)
Patients being treated with fixed CPAP on the basis of APAP titration or being treated with APAP
must have close clinical follow-up to determine treatment effectiveness and safety
A reevaluation and, if necessary, a standard attended CPAP titration should be performed if
symptoms do not resolve or the APAP treatment otherwise appears to lack efficacy

Predictive Equations and Bedpartner Titration

A major prerequisite to the evaluation of different alternative modes of CPAP

titration is a clear picture of what constitutes optimal titration. While we target several
parameters, e.g., elimination of snoring, resolution of defined apneas and hyponeas
or normalization of flow patterns, there is no unambiguously defined gold standard
criterion that can be a universal target. Using predictive equations and bedpartner-
assisted self-titration of CPAP at home are intriguing ideas. In a prospective study
of 1,111 patients Schiza et al. showed that the predicted CPAP pressure calculated
using the Hoffstein formula, which utilizes body mass index, neck circumference
and AHI, was close ±2 cm of water to the pressure obtained by CPAP titration in
79% of the subjects [40]. The authors also tested their own formula which included
the additional variables of smoking history and gender and report a successful
prediction that correlated with the final CPAP pressure in 95% of the subjects.

CPAP Modifications

CPAP tolerance and acceptance can be improved by additional modifications that

include “ramp” function in which the initial pressure is lower than the desired pres-
sure and gradually increases to the desired pressure over a set time frame, presumably
while the patient is falling asleep. Adding humidity to the inspired air can help avoid
150 S. Bhadriraju and N. Collop

nasal dryness. Pressure relief positive airway pressure (PRPAP) is an advanced

technological option to CPAP therapy. Respironics developed the first C-Flex device
(C-Flex™; Respironics, Murraysville, PA, USA). It has three levels of comfort.
The maximum pressure drop is level 3 which is about 3 cmH2O. ResMed (Sydney,
Australia) have developed a similar technology called expiratory pressure relief
(EPR). One study showed that C-Flex™ may improve treatment adherence [41],
while according to another study it was only comparable to traditional CPAP in
terms of efficacy and, at a higher cost [42].
Bilevel PAP involves setting different inspiratory (IPAP) and expiratory pressures
(EPAP). A bilevel setting may be appropriate in patients who have persistent hypoxemia
due to obesity hypoventilation syndrome or intrinsic pulmonary disorders. Bilevel
PAP is typically initiated by using the CPAP level that eliminated the obstructive
apneas as the EPAP and EPAP + 3–5 cm of water as the IPAP. A retrospective analysis
of several studies with a combined number of 719 subjects showed that bilevel PAP
may worsen central apneas in patients with OSA and thus may be less desirable than
CPAP for its treatment [43].

Adherence

Adherence to therapy is a key ingredient of any therapeutic relationship between

health care providers and patients. Patient adherence is modest at best, with any
therapeutic intervention including oral medications for chronic diseases like hyper-
tension. Adherence with CPAP is comparable to other chronic diseases. Older age
and 1 time use of a sedative hypnotic were statistically significant predictors of
compliance with CPAP usage (P < 0.005) [44]. A review of the ethics of compliance
introduces provocative perspectives into the issue of compliance and adherence and
suggests that the debate so far has not taken patient’s perspective into consideration [45].
A broad-based approach that involves the patient as an important component in the
therapeutic decision-making process should be encouraged. A randomized control
trial of 100 patients showed that cognitive behavior therapy (CBT) improved initial
use as well as adherence to CPAP therapy [46].

Conclusion

CPAP is the first-line therapy for OSA. CPAP keeps the airway open by acting as a
pneumatic splint. CPAP treatment of OSA results in several health benefits.
The appropriate pressure that can resolve the upper airway obstruction is classically
derived by a CPAP titration polysomnogram. Predictive equations exist which may
closely approximate the final setting derived by CPAP titration. Autotitrating CPAP,
bilevel PAP, and flexible PAP are some of the modified PAP options.
8 Nasal Continuous Positive Airway Pressure (CPAP) Treatment 151

Summary of Keypoints

• CPAP is the first-line therapy for OSA. CPAP preserves upper airway patency by
acting as a pneumatic splint.
• The appropriate pressure that can resolve the upper airway obstruction is classically
derived by a CPAP titration polysomnogram. Predictive equations do not obviate
the need for a titration study.
• CPAP remains the treatment of choice for patients with OSA.
• CPAP treatment leads to amelioration of several adverse consequences of sleep
apnea including amelioration of daytime sleepiness and decreased rate of motor
vehicle accidents. The effect on cognitive function is less clear.
• Hemodynamic and metabolic benefits of nasal PAP therapy include improved
systemic blood pressure, improved systolic heart function, and decreased cardiac
arrhythmias.
• Adverse effects of PAP therapy include nasal dryness, rhinorrhea, chest discomfort,
facial abrasions, and conjunctivitis. The adverse effects are usually mild and easy
to manage.
• Adherence with nasal CPAP therapy is suboptimal but comparable to other treat-
ments for chronic disease. To optimize adherence, therapeutic decision-making
process should include the patient at every step. CBT may improve initial use as
well as adherence to CPAP therapy.

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Chapter 9
Obstructive Sleep Apnea: Oral Appliances

Peter A. Cistulli, Kate Sutherland, and Andrew S.L. Chan

Keywords Obstructive sleep apnea • Oral appliances • Mandibular advancement

• Dental devices • Upper airway

Introduction

Oral appliances are increasingly being used for the treatment of obstructive sleep
apnea (OSA) and are a simpler alternative to continuous positive airway pressure
(CPAP) [1]. Although CPAP is highly efficacious, the obtrusive nature of the mask
interface results in suboptimal patient compliance, limiting its clinical effectiveness.
This has stimulated interest in alternative treatment strategies which are more accept-
able to patients and oral appliance therapy is one such approach. Oral appliances
protrude and hold the mandible and/or tongue in a forward position. This anatomical
adjustment reduces the propensity for upper airway collapse during sleep through
alteration of airway structure and function. The advantages of this form of therapy
compared to CPAP are simplicity, portability, lack of noise, or need for a power source
and a potentially lower cost. Oral appliances were first described as a treatment for
OSA some 20 years ago. However, the last decade has produced a substantial
evidence base validating their therapeutic use [2]. Oral appliances are now recom-
mended as a first-line therapy for OSA in selected patients and as patient preference
generally favors this form of treatment compared to CPAP, their clinical use will likely
continue to grow in coming years. This chapter will provide an overview of the field.

P.A. Cistulli (*) • K. Sutherland • A.S.L. Chan

Department of Respiratory Medicine, Centre for Sleep Health and Research,
Royal North Shore Hospital, St. Leonards, NSW, Australia
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 155
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_9,
© Springer Science+Business Media, LLC 2012
156 P.A. Cistulli et al.

Types of Appliances

Oral appliances can be categorized by design into two main types; mandibular
advancement splints (MAS) and tongue retaining devices (TRD). MAS attach to the
upper and lower dental arches and mechanically protrude the mandible. TRD feature
a preformed bulb into which the tongue is inserted and held by suction in a protruded
position. Within each of these oral appliance categories there are numerous variations
in design features and specifications.
MAS (also known as mandibular advancement devices or mandibular reposition-
ing appliances) are by far the most commonly used oral appliance for OSA treat-
ment in clinical practice today. Although all appliances of this type maintain the
mandible in a protruded position, there are differences in how this is achieved
between individual designs. Most broadly, MAS can be distinguished by their
configuration as either a one-piece appliance (monobloc) or a two-piece appliance
(duobloc) consisting of separate upper and lower plates. Apart from this design
distinction, appliances differ in size, type of construction material, the amount of
occlusal coverage, degree of customization to a patient’s dentition, amount of verti-
cal and lateral jaw movement permitted, allowance of oral breathing, and degree of
titratability of advancement. The coupling mechanism between the plates of two-
piece appliances can also differ in location and type, from elastic or plastic connectors,
metal pin and tube connectors, hook connectors, acrylic extensions to magnets.
Two-piece appliances have the advantage of greater adjustability and therefore
allow a greater range of mandibular protrusion to be achieved more comfortably;
however, one-piece splints are sometimes indicated due to dental conditions or the
occlusal relationship.
Currently little is known about the influence of these design differences on clinical
outcomes, although such variations are likely to influence efficacy, adverse effects,
and patient compliance and are therefore important in device selection. Compared
to prefabricated “boil and bite” type models, custom-made and adjusted appliances
are associated with better retention in the oral cavity, greater patient comfort, and
efficacy in improvement of OSA [3].
TRD all feature a flexible bulb, which upon insertion of the tongue, can be
squeezed to generate negative suction pressure by the displacement of air. The suction
retains the tongue in a forward position, preventing its collapse back into the
oropharyngeal airway. In original TRD designs, the anterior bulb is fixed to a covering
of the upper and lower dental arches, similar to a mouth guard. These TRD can be
custom-made from impressions of the upper and lower dental arches of individual
patients or be preformed “boil and bite” type appliances which the patient can fit
themselves. A more recent design eliminates the need for any dental coverage as
the bulb is held forward by external vertical flanges placed outside the lips [4].
A role for TRD has been proposed as a treatment option for those patients who are
precluded from MAS therapy due to dental issues (e.g., edentulous patients) as
retention of this appliance is not dependent on the teeth. Furthermore, customized
9 Obstructive Sleep Apnea: Oral Appliances 157

hybrid-type appliances have emerged, which combine an anterior tongue retention

bulb with defined mandibular protrusion achieved through the upper and lower
dental covering [5].

Mechanism of Action

The objective of oral appliance treatment for OSA is to improve airway patency and
prevent upper airway collapse during sleep. MAS have been shown to decrease upper
airway collapsibility [6] and this improvement in upper airway function is dependent
on the advancement of the mandible as control appliances which do not provide any
protrusion are ineffective in reducing apnea-hypopnea index (AHI) [7, 8]. Although
the mechanical advancement of the mandible reduces the propensity of the upper
airway to collapse, by what mechanisms this is achieved is still not well understood.
Intuitively the effect of MAS on the upper airway has been attributed to the forward
movement of the mandible and/or tongue producing increased anteroposterior dimen-
sions of the retrolingual airway. However, recent imaging studies, using techniques
such as magnetic resonance imaging (MRI) and nasopharyngoscopy which allow
visualization of the cross-section of the airway lumen have contradicted this theory
[9, 10]. It appears that the greatest effect of MAS on upper airway structure is in the
velopharynx, behind the soft palate. Furthermore, the largest increase in airway
diameter occurs in the lateral, not anteroposterior, dimension [10]. Although initially
counterintuitive, soft tissue connections exist between the mandible, tongue, and lateral
pharyngeal walls and soft palate within the palatoglossal and palatopharyngeal
arches. The stretching of these connections by mandibular advancement has been
proposed as a potential mechanism by which MAS increases velopharygeal patency
and stability. Upper airway structural changes with MAS are illustrated in Fig. 9.1.
In addition to these anatomical effects it is possible that MAS may influence
upper airway neuromuscular function. Research studies have demonstrated an
increase in genioglossus muscle activity with MAS [11, 12]. Although the data is
limited, stimulation of neuromuscular reflex pathways by MAS may further contribute
to upper airway stability during sleep. The relative importance of anatomical vs.
neuromuscular responses to MAS may also vary between individual patients.
The mechanisms of action of the more infrequently used TRD appliances have
received even less attention although they likely differ from that of MAS. TRD
increases upper airway dimensions to a greater extent than MAS due to the greater
anterior movement of tissue produced by retaining the tongue outside the oral cavity
[13]. The relevance of these greater structural effects with TSD to treatment efficacy
warrants further study. In this MRI study, although TSD was shown to increase
retrolingual dimensions, the greatest impact on airway structure was in the velopharynx.
Velopharyngeal volume was increased by expansion of both the lateral and antero-
posterior diameters, suggesting that in addition to forward displacement of the
158 P.A. Cistulli et al.

Fig. 9.1 Mechanisms of action of MAS. Upper airway volume is increased with MAS. This change
in airway structure is associated with movement of surrounding soft tissue structures. Analysis of
the movement of soft tissue centroids (a point analogous to the center of mass of a 3D structure)
shows anterior displacement of the tongue base muscles and lateral movement of the parapharyngeal
fat pads away from the airway with MAS wear

tongue, stretching of other soft tissue connections may contribute to enlarging other
dimensions of the upper airway. Moreover, it is possible to TRD counteract the
effect of gravity on the tongue in the supine position.

Efficacy and Effectiveness in the Treatment of OSA

That MAS are able to significantly improve OSA across a range of severities has
now been established by multiple randomized controlled trials. Several recent
systematic reviews of the efficacy and effectiveness of MAS also exist [14–17].

Impact on Polysomnographic Outcomes

Success rates in reducing AHI obviously vary with the definition of success used.
The inclusion of a rigorous definition of treatment success seems most appropriate
9 Obstructive Sleep Apnea: Oral Appliances 159

given that resolution of OSA is the ultimate goal of treatment. By stringent definition
of a complete response (reduction of AHI to less than 5/h), 35–40% of patients
achieve treatment success. However, a further 25% display a partial response with a
reduction in AHI of greater than 50% but with a residual AHI remaining above 5/h.
Approximately 35–40% of patients will not respond to treatment (less than 50%
AHI reduction) and some patients experience an elevation in AHI with MAS treatment
[7, 8, 18, 19]. However, as these figures indicate, around two-thirds of patients will
receive clinical benefit from MAS therapy.
Improvements in other polysomnographic indices have also been demonstrated
with MAS. Measures of oxygen saturation generally show some improvement [20, 21],
although the changes are less impressive than the effects on AHI, with oxygen
saturation rarely increased to normal levels. Improvements in sleep architecture [7]
and arousal indices [8, 20, 22] are also demonstrated.

Impact on Health Outcomes

The effects of MAS on daytime sleepiness have mostly been assessed subjectively
using the Epworth Sleepiness Scale. Although generally improvements in Epworth
Sleepiness scores are observed [23–25] the magnitude is often small and some studies
have identified a placebo effect on subjective sleepiness with use of an inactive oral
appliance [7, 8]. Studies including objective measures of sleepiness are more limited,
but MAS appears to have equivalent effects to CPAP with regard to performance in
the maintenance of wakefulness test (MWT) [25, 26] and the Oxford sleep resis-
tance (OSLER) test [23]. MAS have also been shown to improve simulated driving
performance to a similar extent to CPAP [27].
The effects of MAS on neurocognitive functioning have only been assessed in a
small number of studies and warrant further investigation. Compared to an inactive
oral appliance, MAS treatment improved performance in tests of vigilance/psycho-
motor speed but did not change other neurocognitive measures [28]. Other studies
have reported MAS to produce similar effects to CPAP on some neuropsychological
measures [23, 25, 26], but not others [23, 25]. Quality of life, measured by validated
questionnaire, is also improved with MAS compared to placebo tablet [25].
The potential to modify cardiovascular outcomes is an important goal of any
treatment for OSA as the disorder is associated with increased risk of cardiovascular
morbidity and mortality. Modest reductions in blood pressure following MAS
treatment have been reported in uncontrolled studies [29, 30]. Two randomized
placebo-controlled trials, using intention to treat analyses, have also reported a
blood pressure reduction of similar magnitude (2–4 mmHg) after MAS treatment
for periods of 1 and 3 months [18, 25]. The effect of MAS treatment in regards to
cardiovascular endpoints, such as cardiovascular events and mortality, are yet to be
investigated. However, indications that there may be a positive impact have been
shown in studies investigating intermediate endpoints. One study has shown
improvement in oxidative stress and endothelial function after 1 year of MAS treatment
160 P.A. Cistulli et al.

for OSA [31]. A subsequent investigation has shown improved endothelial function
after 2 months of MAS treatment, to the same extent as that seen with CPAP in this
crossover study [32].

Long-Term Efficacy

Less is known about the efficacy and effectiveness of MAS therapy long term.
However, studies reevaluating patients between 1 and 5 years after initiation of
treatment indicate a reasonably high rate of sustained control of OSA [21, 33, 34].
The main reasons for relapse can be attributed to appliance failure due to wear and
tear, with patients who have replaced or adjusted their appliance faring better long
term [33]. Weight gain may over time also decrease efficacy [35] and these issues
highlight the need for long-term dental and medical follow-up.

Effectiveness Compared with Other Treatments

As the current gold standard for OSA treatment, CPAP is highly efficacious and
cross-over trials comparing MAS to CPAP consistently find that MAS is less effica-
cious in improving the polysomnographic measures of OSA [25, 26, 36, 37].
However, although CPAP is superior in reducing AHI and improving oxygen satu-
ration, similar improvements in health outcomes suggest MAS may not be inferior
to CPAP in clinical practice. For example, several randomized controlled trials have
reported similar reductions in blood pressure despite inferiority of MAS in normal-
izing polysomnographic indices [25, 38]. Although CPAP is highly efficacious,
tolerance and adherence are often low and it is known that patient preference gener-
ally lies in favor of oral appliances. This raises the possibility that the superior
efficacy of CPAP is mitigated by inferior compliance, resulting in MAS and CPAP
having overall similar effectiveness in the clinical setting. A summary of published
randomized cross-over studies of CPAP vs. MAS is shown in Table 9.1.
TRD are used less commonly than MAS and investigations into their efficacy as
a treatment for OSA remain limited [4, 22, 39, 40]. A recent randomized cross-over
study comparing MAS and TSD found similar reductions in AHI with both appli-
ances; however, patient tolerance and subjective compliance was less with TRD and
patient preference favored MAS [22]. The focus of the remainder of this chapter
will be MAS as TRD are rarely used in clinical practice.
Comparisons of surgical treatments for OSA are sparse. A randomized trial com-
paring MAS with surgical treatment (uvulopalatopharyngoplasty) found that MAS
had higher success rates in improving OSA and this greater effectiveness of MAS in
AHI reduction was evident at both 1 and 5 years follow-up [34].
 9

Table 9.1 Efficacy of MAS vs. CPAP: summary of published randomized crossover studies
Study recruitment Treatment efficacy
Inclusion criteria Treatment AHI (/h) P value MAS Treatment
Study (first author, year) AHI (/h) No. (% males) interval BASELINE AHI (/h) CPAP AHI (/h) MAS vs. CPAP preference
Clark, 1996 [65] ³15 23 (100%) 2 weeks 38.9 ± 14.3 11.2 ± 3.9a 19.9 ± 12.7a N/A MAS
Ferguson, 1996 [66] 15–50 27 (89%) 4 months 19.7 ± 13.8 3.5 ± 1.6a 9.7 ± 7.3a <0.05 MAS
Obstructive Sleep Apnea: Oral Appliances

Ferguson, 1997 [66] 15–55 24 (79%) 4 months 25.3 ± 15.0 4.0 ± 2.2a 14.2 ± 14.7a <0.05 MAS
Engleman, 2002 [26] ³5 51 (76%) 8 weeks 31 ± 26 8 ± 6a 15 ± 16a <0.01 CPAP
Randerath, 2002 [36] 5–30 20 (80%) 6 weeks 17.5 ± 7.7 3.2 ± 2.9a 13.8 ± 11.1a <0.01 MAS
Tan, 2002 [37] <50 24 (83%) 2 months 22.2 ± 9.6 3.1 ± 2.8a 13.8 ± 11.1a NS MAS
Barnes, 2004 [25] 5–30 104 (80%) 3 months 21.3 ± 1.3 4.8 ± 0.5a 14.0 ± 1.1a <0.05 CPAP
Hoekema, 2008 [67] ³5 103 (89%) 2–3 months 39 ± 4.3 2.4 ± 4.2a 7.8 ± 14.4a NS N/A
Gagnadoux, 2009 [23] 10–60 59 (78%) 8 weeks 34 ± 13 2 (1–8) 6 (1–8) <0.001 MAS
AHI values = Mean ± SD except Gagnadoux, 2009 = median (interquartile range)
a
p < 0.05 compared to baseline
161
162 P.A. Cistulli et al.

Patient Selection and Prediction of Treatment Outcome

Indications for Treatment

In 2006 the American Academy of Sleep Medicine (AASM) published an update to

their clinical practice parameters for the use of oral appliances for the treatment of
OSA [2]. These parameters state that oral appliances are indicated for patients with
mild to moderate OSA who prefer an oral appliance over CPAP, or in those who are
do not respond to CPAP, are not appropriate candidates for CPAP, or who fail treatment
attempts with either CPAP or behavioral measures (e.g., weight loss or positional
therapy). It is recommended that patients with severe OSA initially trial CPAP before
considering oral appliance treatment based on the superior efficacy of CPAP.

Oral Considerations

Dental considerations are the initial limiting factor in patient selection for MAS
treatment. Patients must have enough teeth to permit adequate retention of the appli-
ance, not have temporomandibular joint problems and have sufficient dental health.
The use of an oral appliance may result in excessive tooth movement which is an
issue in periodontal disease. Also partial denture patients may experience loosening
of their dentures due to tooth movements induced by the splint. Although the evidence
is not strong, it has been suggested that limited mandibular protrusion (<6 mm) is
also a contraindication. One study has suggested that up to a third of patients are
excluded on the basis of these dental factors [41].

Indicators of Treatment Success

Beyond the initial dental requirements, patient selection criteria are not necessarily
straightforward. A number of factors have been associated with treatment success
and are summarized in Table 9.2.
Firstly information from diagnostic sleep studies may aid in patient selection.
There is a general belief that increasing OSA severity is associated with treatment
failure, although notable exceptions do exist [7, 8]. It has also been reported that
MAS has a greater effect on supine compared to lateral AHI and therefore may be
more effective in patients with positional OSA [35, 42]. Studies have reported a
better treatment response with younger age, lower body mass index, and smaller
neck circumference [7, 35]. Female gender has also been suggested to be favorable
for treatment success [35]; however, this has not been adequately addressed with
prediction studies conducted in predominantly male samples.
Craniofacial factors may be related to treatment response with imaging studies
reporting cephalometric variables such as a longer maxilla, smaller overjet, shorter
soft palate, distance between mandibular plane and hyoid bone, retropalatal airway
9 Obstructive Sleep Apnea: Oral Appliances 163

Table 9.2 Predictors of favorable outcome with MAS treatment

Demographic/anthropometric Polysomnographic
• Younger age • Lower baseline AHI
• Female gender • Supine-dependent OSA
• Lower BMI
• Smaller neck circumference
Physiological Cephalometric
• Oropharyngeal collapse • Smaller airway space
• Lower nasal resistance • Shorter soft palate
• Airway patency during Müller • Greater distance between hyoid and mandibular plane
maneuver following mandibular • Narrower SNB angle
advancement • Wider SNA angle

space and facial height as relating to a positive outcome [7, 43, 44]. Additionally,
functional characteristics of the upper airway may be associated with MAS treatment
response. Patients who primarily collapse their upper airway in the oropharyngeal
region during sleep are more likely to be MAS responders compared to patients
displaying primary velopharyngeal airway collapse [45]. OSA patients with lower
nasal resistance may also respond more favorably to MAS therapy [46].
Research studies collectively suggest that treatment outcome relates to anthropo-
metric, polysomnographic, physiologic, and anatomical characteristics. However,
these potential predictive factors of MAS treatment success have generally not
been assessed in prospective studies. Therefore, there is still considerable doubt
about the validity and utility of using these factors to aid in patient selection in the
clinical practice setting.

Techniques for Predicting Outcome

A consistent finding of all MAS efficacy studies is that not all patients will respond
to this form of treatment. There is significant wastage of health resources associated
with implementing this form of therapy in patients who will ultimately not experience
any clinical benefit. The ability to prospectively identify which patients are likely to
respond to MAS therapy is therefore of key importance. Various imaging and physi-
ological techniques have been employed in research studies to identify anatomical
and functional characteristics associated with MAS treatment outcome.
Investigations during sleep have identified primary oropharyngeal collapse, mea-
sured by a multisensor pharyngeal catheter, as a highly predictive of treatment success
[6]. Nasopharyngoscopy during drug-induced sleep showed improved airway patency
with simulated mandibular advancement to be indicative of treatment success [47].
However, such assessments during sleep are generally not feasible to perform in clinical
practice. A study comparing polysomnographic outcomes of a thermoplastic “boil
and bite” appliance to a custom-made and fitted appliance has found that treatment
164 P.A. Cistulli et al.

response with the less-efficacious disposable appliance could not be used to predict
response to the customized appliance [3]. However, single-night titration protocols
(see appliance titration protocols) may have some predictive utility.
Three-dimensional imaging modalities have been used to view the effects of
mandibular advancement on the upper airway during wakefulness. Ultra-fast MRI
has demonstrated persistence of airway collapse with mandibular advancement
during the Müller maneuver to be indicative of treatment failure [48]. MAS treat-
ment responders also appear to have larger dimensional increases in the upper airway
with mandibular advancement in static MR images, compared to nonresponders,
particularly in the lateral diameter of the velopharynx (Fig. 9.2) [10].
In the clinical setting, prediction techniques must be simple, widely available,
and cost-effective. Expensive assessments must be balanced against the cost of
simply constructing an appliance to observe the outcome. Lateral cephalometric
radiographs can provide information about craniofacial morphology which may be
relevant to MAS treatment outcome. However, 3D imaging studies suggest airway
changes in the lateral dimension are most pertinent to MAS treatment response
which may limit the predictive utility of lateral cephalometry. Nasopharyngoscopy
allows evaluation of changes in airway caliber and real-time imaging additionally
facilitates evaluation of airway functional properties (e.g., compliance). In a nasophar-
yngoscopic study during wakefulness [9] a greater increase in velopharyngeal cross-
sectional area during the Müller maneuver was demonstrated in responders compared
to nonresponders with mandibular advancement. Awake nasal resistance has also
been found to be lower in MAS responders; however, overlapping values between
treatment response groups exclude determination of a reliable cut-off value for use
in individual patients [46]. Flow-volume curves (obtained by standard spirometry)
have been identified as a surrogate marker for the site of upper airway collapse during
sleep [49]. A study of 54 OSA patients undergoing oral appliance treatment demon-
strated a significantly lower inspiratory flow rate at 50% of vital capacity (MIF50)
and higher expiratory flow rate at 50% of vital capacity (MEF50)/MIF50 ratio in
responders compared to nonresponders and derived cut-off values had a sensitivity
of 91% and specificity of 88% in predicting treatment success.
There is still a long way to go in the development of accurate and reliable prediction
techniques before introduction into routine clinical practice. Prediction techniques
must be prospectively validated before recommendation for clinical use and this
is generally lacking for most MAS prediction models proposed in the litera-
ture. A prospective validation study of the flow-volume loop prediction method was
undertaken in 35 newly diagnosed OSA patients before commencing MAS treatment
[50]. In this prospective study only 48.6% of patients were correctly classified using
the previously derived cut-off values. It is likely that the degraded performance of
the prediction model is a reflection of the complex multifactorial nature of the upper
airway response to MAS treatment. It may be that a single structural or functional
assessment is inadequate, especially considering that the relative importance of
these factors to treatment outcome is likely to vary between individuals. It may
prove that a combination of structural and functional assessments is needed to accu-
rately predict MAS treatment outcome in individual patients.
9 Obstructive Sleep Apnea: Oral Appliances 165

Fig. 9.2 Magnetic resonance imaging comparison of the upper airway with and without MAS in
a treatment responder and nonresponder. An increase in airway cross-sectional area with MAS can
be seen in the axial slice of a MAS treatment responder (posttreatment AHI <5/h). The responder
shows an increase in total upper airway volume with MAS compared to without MAS. The most
significant changes are in velopharynx and in the lateral, rather than the anteroposterior (AP)
dimension. Upper airway analysis of a nonresponder (<50% reduction in posttreatment AHI)
shows no increase in upper airway dimensions and, in fact, a slight decrease in upper airway
volume occurs when the MAS is in place in this particular patient
166 P.A. Cistulli et al.

Contraindications

Oral appliances have no known role in treating central sleep apnea or hypoventilation
syndromes and therefore should be reserved solely for the treatment of OSA. CPAP
should be preferentially implemented in cases where urgent treatment is required to
control severe symptoms (such as sleepiness whilst driving) or medical comorbidities
because of the extended acclimatization period required for oral appliance therapy.

Appliance Titration Protocols

Determining the amount of mandibular advancement needed to prevent occurrence

of apneas and hypopneas is not straightforward as there does not always appear to
be a direct correlation between degree of protrusion and therapeutic efficacy.
The level of mandibular advancement that is optimally efficacious is likely to
depend on the specific pathophysiological traits which predispose the individual to
OSA in the first place. Therefore, factors such as craniofacial morphology and upper
airway structure and function may influence the therapeutic “dose” of mandibular
protrusion that is required. Optimal advancement therefore varies considerably from
patient to patient, analogous to individual pressure requirements for CPAP users.
However, greater levels of advancement generally appear to be more efficacious
[24, 51] and therefore advancement to the maximum limit which the patient can be
comfortably tolerated would seem most appropriate. Reported levels of clinically
efficacious advancement are in the range of 50–90% of maximum voluntary protru-
sion [7, 8, 18, 19].
Patient tolerance to MAS increases with wear. Therefore, titratable appliances,
which allow incremental advancements over time, offer a clear advantage in their
ability to accommodate such adaptation. The standard approach to implementation
of MAS is an initial 4-week period of acclimatization followed by an additional
8–12 weeks in which the appliance is incrementally titrated. Although this process
optimizes therapeutic benefit, the associated time delay is inappropriate for patients
who require rapid treatment (e.g., those who are severely symptomatic or have
cardiovascular co-morbities). In such cases CPAP, which can be implemented
immediately, would be the preferred treatment option.
Although titration generally occurs systematically under the direction of a dentist,
some studies have assessed patient self-titration protocols. In these cases, patients
were either able to adjust their own appliance at home guided by subjective symptom
assessment vs. comfort levels [52] or increments were only made beyond the initial
advancement level (70–80% of maximum) at the patient’s request [53]. Treatment
efficacy in these studies was in accordance with levels seen in those using full
titration protocols. Such methods have the potential to reduce the number of time-
consuming titration visits which may be a deterrent to some patients in accepting
this form of therapy. Assessment of the efficacy of home-titrated advancement by
9 Obstructive Sleep Apnea: Oral Appliances 167

polysomnography showed that of the patients successfully treated with MAS, 79%
were treated at their self-titration level without need for further advancement [52].
Recently, several studies have emerged which explore single-night titration
protocols to determine the degree of mandibular advancement which best eliminates
respiratory events [23, 54, 55]. The method consists of fitting the patient with a
temporary oral appliance which is attached to a hydraulic or motorized advancement
mechanism to protrude the lower plate. The degree of advancement can then be
controlled remotely via a computer interface without waking the patient. The possibility
of single-night titration is highly attractive in that there is the potential to immedi-
ately ascertain the extent of therapeutic benefit to a patient, as well as the degree of
protrusion needed to achieve this. However, a limitation of this approach may be
that without the gradual build-up of tolerance, the required “dose” of mandibular
advancement may not be achievable within a single night without subjecting the
patient to discomfort.

Adverse Effects

MAS improve OSA through the changes in airway configuration caused by passively
holding the mandible in a more anterior position. By nature, moving the mandible
forward via an intra-oral appliance exerts reciprocal forces on the teeth and jaw, and
may also apply pressure on the gums and oral mucosa depending on the appliance
design. These mechanical effects can result in acute symptoms, as well as long-term
dental and skeletal changes. Side effects and complications can occur at any stage
during treatment and are generally thought to be minor in nature, although more
severe and continuing side effects can lead to cessation of appliance use. Common
adverse effects of oral appliance therapy are summarized in Table 9.3.
Side effects are common at the initiation of treatment and during the acclimatiza-
tion period as would be expected. However, these are generally described as mild
and temporary and only occasional lead to discontinuation of use of the appliance.
The most commonly reported adverse effects are excessive salivation, mouth dry-
ness, tooth pain, gum irritation, headaches, temporomandibular joint discomfort,
and morning after occlusal changes. A pooled side-effect profile from multiple studies
suggests 6–86% of patients will experience at least one of these side effects [14].
Differences in the reported incidences of short-term adverse effects probably relates
to differences in the appliance used, degree of mandibular advancement, frequency
and duration of follow-up, and the expertise of the dentist involved in these studies.
Early recognition and attention to such adverse symptoms are important as they
have the potential to influence the patient’s ultimate acceptance of the treatment.
Resolution of symptoms usually occurs within several days to several weeks with
regular use and occasional adjustment of the appliance for fit [15].
More severe and continuing adverse symptoms include temporomandibular
joint pain, myofascial pain, tooth and gum pain, dry mouth, and salivation [14].
Observations from collective studies place the occurrence of on-going effects in the
168 P.A. Cistulli et al.

Table 9.3 Adverse effects associated with MAS use

Short-term Long-term
• Dental discomfort (especially upper and lower incisors) • Occlusal changes
• Temporomandibular joint pain • Increased facial height
• Mouth dryness • Increased mouth opening
• Salivation • Increased mandibular plane
• Gum irritation angle
• Bruxism • Changes in inclination of
incisors

range of 0–75%, but again, differences in oral appliances design and implementation
may account for the varying rates. These symptoms may occasionally lead to
discontinuation of use of the appliance.
Dental and skeletal changes are evident with long-term use of MAS. Data now
exists from studies which have monitored patients up to 7 years after initiation of
MAS therapy. Changes in occlusal contact area have been identified with long-term
use [56] and increased facial height, mouth opening, and changes in the inclination
of the incisors have also been reported [57–59]. Duration of wear of the oral appliance
tends to correlate with the extent of changes in the bite relationship and mandibular
posture [60, 61]. However, favorable occlusive changes have been reported in 41%
of patients, with some patients showing no change at all (14%) [60]. Orthodontic
changes and the desirability of such changes may be predicted on the basis of
pretreatment dental characteristics [60, 62]. For example, a greater overbite at baseline
has been reported to be associated with both smaller and more favorable orthodontic
changes. The influence of different device designs on occlusal relationships has not
been thoroughly investigated; however, a soft elastomeric device has been shown to
induce smaller effects compared to a hard acrylic device [62]. Generally, these
changes are minor or even subclinical and it is uncommon that it will be necessary
to cease treatment on this basis. However, should significant occlusal changes occur,
the decision to discontinue this form of therapy should be weighed against the
degree of this change, the severity of OSA and the feasibility of treatment alterna-
tives such as CPAP.
Preliminary evidence from a small randomized controlled trial suggests daily
jaw exercises improve occlusal contact area and bite force. Such exercises may
relieve masticatory muscle stiffness and facilitate movement of the mandible to its
normal position and therefore be a potential method to help minimize occlusal
changes in predisposed patients [63].

Treatment Adherence

Adherence to oral appliance treatment depends on the balance between the perceived
benefit of treatment vs. the side effects experienced. A variety of factors can influence
tolerance particularly during the initiation of therapy, and these include adequate
9 Obstructive Sleep Apnea: Oral Appliances 169

communication, initial frequent monitoring, and appropriate design and fit of the
appliance for the individual. Patients need to be fully informed of the possible
discomfort and the importance of the acclimatization period.
Unlike CPAP compliance, which can be objectively monitored via download of
usage data from the machine, there is currently no commercially available method
for objectively measuring MAS adherence in clinical practice. Therefore, most
compliance data in the literature are based on self-report. A summation of subjec-
tive compliance data from multiple studies suggests on average 77% of patients still
use the appliance at 1 year [14]. One study has employed a novel intra-oral device
which utilizes embedded temperature sensors to objectively monitor compliance
[64]. Data indicated that on average patients used the appliance for 6.8 h per night
(with a range of 5.6–7.5 h) which is similar to figures from studies using subjective
reports. As greater MAS compliance rates relative to CPAP are likely to be a factor
equilibrating health outcomes between the two treatments, there is a need for tech-
nological advances and studies to objectively evaluate this issue.

Interdisciplinary Care Model

As MAS is a dental-based treatment for a medical sleep disorder, a multidisciplinary

care approach is necessary. A sleep physician and dental practitioner with expertise
in the management of sleep disordered breathing are required to effectively implement
oral appliance therapy for OSA and enhance patient outcomes. Therefore, commu-
nication between disciplines and planning along a coordinated treatment pathway
that is also accessible to and understood by patients is integral to successful
outcomes. It is recommended that the therapeutic efficacy of oral appliance therapy
is objectively assessed in all patients by polysomnography or an attended cardio-
respiratory (Type 3) sleep study with the oral appliance in place after final adjustments
of fit have been made. This is based on reported associations of even mild OSA with
adverse health outcomes, especially in patients with comorbid disease or risk factors
and additionally, that some patients are known to experience an increase in AHI
while using an oral appliance. Ongoing review and care in both medical and dental
settings is required to assess compliance, comfort, and fit of the device as well as
monitoring of treatment efficacy and side effects.

Future Research

Although a role for oral appliances in the treatment of OSA is now well established,
there are still key unresolved issues that need to be addressed by future research.
• Prediction methods for patient selection. The current lack of a valid and reliable
prediction method for treatment outcome represents a major barrier to the wide-
spread adoption of this treatment modality in clinical practice. It is hoped that
170 P.A. Cistulli et al.

ongoing research will identify patient subgroups with greater likelihood of treatment
success. The most accurate prediction method may incorporate several functional
and structural assessments from an individual patient into an overall prediction
model.
• Objective compliance monitoring. The development of technologies that can
objectively monitor nightly oral appliance use, as can be done with CPAP, will be
essential in research and clinical practice.
• Influence of different appliances and designs. The influence of different appliance
design on treatment outcome and side effects is not clear. Comparative studies
are essential to define the design features that optimize outcomes.
• Simplification of titration procedures. Current titration procedures require
significant time to reach the point of optimal treatment efficacy and represent a
significant barrier to implementation of this therapy particularly in symptomatic
patients. Single-night titration protocols may offer hope in this regard.
• Clinical effectiveness for modifying adverse health outcomes of OSA. Although
recent studies leave little doubt about the short-term efficacy of oral appliances,
there is a need for long-term follow-up studies, particularly in regard to the
effects of MAS on the health consequences of OSA. The clinical effectiveness of
MAS in modifying these factors also needs to be compared with CPAP.
• Long-term efficacy and adverse effects. As OSA is often a lifelong condition,
treatment needs to be effective long term. There is a need for longitudinal studies
of efficacy and the factors affecting this, as well as potential adverse effects.

Conclusion

Oral appliances are increasingly being used to treat OSA. MAS are the most common
type of appliance used in clinical practice. Robust evidence of the efficacy of oral
appliances for improving polysomnographic indices and modifying health risks
associated with OSA has emerged over the last decade. Although CPAP has greater
overall efficacy compared to MAS, patients generally prefer MAS and therefore
differences in adherence profiles between the two treatments may level their effi-
cacy in clinical practice. Side effects such as excessive salivation, muscle and tooth
discomfort are common during the initial treatment stages but are most often minor
and abate with continued use. Longer term effects of MAS wear, such as tooth
movement and malocclusion, occur in a significant number of patients but are usually
minor in nature and do not require cessation of treatment.

Summary of Keypoints

• Oral appliances are increasingly being used for the treatment of OSA with the
most common appliance type being those which hold the mandible in a protruded
position (MAS).
9 Obstructive Sleep Apnea: Oral Appliances 171

• Although individual appliance designs vary, the advancement of the mandible is

key to their effectiveness in reducing upper airway collapsibility during sleep.
• Oral appliances can be effective in treating a range of OSA severities with around
two-thirds of patients achieving a clinically important response and complete
resolution of OSA (AHI reduced <5/h) occurring in around 40% of patients.
• Although oral appliances are less efficacious in reducing polysomnographic
indices of OSA compared to CPAP similar improvements in health outcomes
suggest that the superiority of CPAP in improving oxygen desaturations and AHI
may be mitigated by inferior compliance, resulting in both treatments having
overall similar effectiveness in the clinical setting.
• Various factors have been associated with greater likelihood of treatment success
such as female gender, younger age, supine-dependent OSA, lower BMI, smaller
neck circumference, and craniofacial factors.
• Short-term side effects (such as discomfort and excessive salivation) are
common but usually minor and transient and long-term dental changes appear to
be generally minor.
• Long-term side effects include tooth movements, although only occasionally
warranting cessation of therapy. Patients should be informed of this possibility
before embarking on treatment.
• As oral appliances are a dental-based treatment for a medical sleep disorder, a
multidisciplinary care approach is necessary. Collaboration between sleep
physicians and dental practitioners, for diagnosis and treatment is recommended
to effectively implement oral appliance therapy for OSA and enhance patient
outcomes.

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67. Hoekema A et al. Obstructive sleep apnea therapy. J Dent Res. 2008;87(9):882–7.
Chapter 10
Obstructive Sleep Apnea: Surgery

Ryan J. Soose and Patrick J. Strollo

Keywords Obstructive sleep apnea • Positive airway pressure therapy • Airway

reconstructive surgery • Uvulopalatopharyngoplasty • Sleep disorders • Snoring
• Nasal surgery • Allergic rhinitis • Expansion sphincter pharyngoplasty • Transpalatal
advancement surgery • Hypopharygneal surgery • Maxillomandibular advancement
surgery

Introduction

Obstructive sleep apnea (OSA) is, for most patients, a chronic condition that will
require management across the lifespan. Like most chronic diseases, prevention
of OSA remains the ideal and most attractive treatment from a public health
perspective. At this juncture, however, management of the large population of
patients diagnosed with sleep-related breathing disorders (as well as those who are
still undiagnosed), remains the critical focus of most sleep physicians. As with
hypertension, diabetes, and other chronic conditions, the individual treatment plan
is not aimed at “cure,” but rather (1) symptom and quality of life improvement and
(2) reduction of cardiovascular and general health risk.
Both physician and patient understanding of OSA in this context is the corner-
stone for successful management. This approach allows for customization of each

R.J. Soose (*)

Division of Sleep Surgery, Department of Otolaryngology, University of Pittsburgh Medical
Center, UPMC Mercy Building D, Suite 2100, 1400 Locust Street, Pittsburgh, PA 15219, USA
e-mail: [email protected]
P.J. Strollo
Division of Pulmonary, Allergy and Critical Care Medicine, UPMC Sleep Medicine Center,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 175
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_10,
© Springer Science+Business Media, LLC 2012
176 R.J. Soose and P.J. Strollo

individual’s treatment plan depending on their symptoms, airway anatomy, disease

severity, and medical comorbities. Across the lifespan, the same patient, with the
same AHI, may benefit from different treatment options, or a combination of
treatment options, depending on the clinical context at that particular stage of life.
It is imperative to treat the patient, not just the AHI.
In its simplest form, OSA is characterized by an upper airway that is too narrow
and/or too collapsible. As such, upper airway reconstructive surgery certainly can
and should play a role in the treatment of patients with this upper airway disease,
particularly those who fail treatment with other medical device therapies. Proper
management of OSA in the twenty-first century requires the ability to obtain a
proper sleep history, to thoroughly examine each individual’s unique airway
anatomy, and to be at least familiar with a variety of both medical and surgical treat-
ment options. Positive airway pressure (PAP) therapy remains the most attractive
first-line treatment and an excellent long-term management strategy for many
patients given its effectiveness, low morbidity, and reversibility. Acceptance and
long-term compliance rates with PAP therapy are suboptimal, particularly in certain
subgroups such as patients who are younger, not sleepy, have milder disease, and/or
have symptomatic nasal obstruction. Without other treatment options, millions of
OSA patients will continue to suffer from the symptoms and cardiovascular morbidity
associated with this disease.
The aim of this chapter is to provide the sleep medicine practitioner with a general
overview of the approach to the sleep patient from a surgical/anatomical perspective
with discussions on the importance of examining the upper airway, recognizing
different airway phenotypes, and understanding the role of upper airway reconstruc-
tive surgery with its unique challenges and future directions; rather than providing
a list of available surgical techniques, which often vary by surgeon/region and are
currently rapidly evolving.

Clinical Evaluation

Background and Clinical Context of Surgical Therapy

Device treatments, such as PAP therapy or an oral appliance, are critically dependent
on regular continued daily application to replicate the results recorded in the very
limited time observed in the sleep laboratory setting. One must be cautious when
translating the reduction of the AHI and improvement of other objective sleep
measures with PAP therapy on a couple of hours of sleep on a therapeutic poly-
somnogram into real-life clinical efficacy, although data management software is
available that allows clinicians to assess longitudinal control of the AHI. It is still
unclear what the effect of partial usage is on long-term reduction of cardiovascular
risk and what level of device compliance is necessary to achieve acceptable disease
management [1].
Surgical therapy differs in this regard, in that it does not depend on usage or
compliance. In fact, it is this aspect that is often attractive to patients. Nevertheless,
10 Obstructive Sleep Apnea: Surgery 177

surgery presents its own challenges in determining what defines successful management.
The nature of surgical therapy lends itself to judgment by AHI criteria before and
after the surgical intervention – a measurement that often poorly reflects the actual
clinical outcome and whether the goals of surgical therapy were achieved. For
research purposes, arbitrary AHI criteria have been used to define adequate surgical
therapy, for example, AHI <20 with at least a 50% reduction in the AHI [2]. The
specific improvement in PSG criteria necessary for symptom improvement and
reduction of cardiovascular risk is still largely unknown and likely varies greatly
from patient to patient. Unfortunately, despite its past use as the primary marker of
surgical success, the AHI is only one metric of disease severity and overall corre-
lates poorly with patient symptoms, general health and sleep-related quality of life
measures, and performance on psychomotor vigilance testing [3].
The following patient examples below illustrate this point, and a glimpse of the
much larger problem of determining what defines successful surgical management.
1. Patient 1 undergoes surgical therapy for severe OSA, and has an AHI reduction
from 100 to 24. Postoperatively he has resolution of his loud snoring, nocturnal
awakenings, and daytime sleepiness. His blood pressure is also under better
control with less medication.
2. Patient 2 undergoes surgical therapy for moderate OSA, and has an AHI reduction
from 29 to 14. Postoperatively he complains of persistent snoring and excessive
daytime sleepiness.
By historical measures of surgical “success,” the problem with evaluating AHI
alone is quite clear, where Patient 1 would be considered a treatment failure
while Patient 2 is documented as treatment success. Although the exact criteria for
delineating successful management of patients with sleep apnea is still unknown,
the inadequacy of AHI analysis alone must be recognized.
Evaluating the effectiveness of surgical therapy is further complicated by the
wide variety of procedures and different surgical techniques available, as well as
the ethical and practical concerns with instituting randomized controlled sham-
procedure studies. Nevertheless, it is clear that airway reconstructive surgery has
benefits in many patients with OSA. A recent large Veterans Administration (VA)
population study showed a 31% reduced mortality rate in OSA patients treated
with uvulopalatopharyngoplasty (UPPP) compared to those treated with CPAP,
even after controlling for medical comorbidities and other clinical factors [4]. In no
way does this suggest that UPPP is more effective than CPAP; rather, it suggests
that, across a population, reduction in disease severity with surgical therapy may be
as effective in improving quality of life and overall morbidity as a medical therapy
device with significant non-adherence concerns.

Role of Surgical Therapy

For the millions of patients who will not accept or cannot tolerate PAP therapy or
who have compliance rates that are suboptimal for clinical success, surgical therapy
178 R.J. Soose and P.J. Strollo

can provide a method of symptom and quality of life improvement in addition to a

reduction in cardiovascular risk. Besides sole therapy, surgery also can play an
effective role as part of combination therapy and an adjunct to medical treatment.
For example, as referenced later, surgical treatment of symptomatic nasal obstruc-
tion can reduce PAP pressure requirements, improve PAP compliance, and improve
tolerance of an oral appliance.
The surgical treatment of OSA has evolved rapidly over the last decade. Better
understanding of the pathophysiology of OSA and improved methods of airway
evaluation, such as sleep endoscopy, and a better understanding of patterns of
obstruction have led to new surgical approaches. In the past, patients intolerant to
PAP therapy were typically offered traditional palatal surgery with relatively poor
overall success rates. Those who failed to improve were then offered more morbid
but potentially more effective skeletal surgery. The current paradigm avoids this
“cookie-cutter” approach and instead relies on specifically identifying and treating
each individual’s unique pattern of airway obstruction. New evidence-based
techniques with improved results, lower morbidity, and faster recovery are now
available and are quickly relegating the traditional UPPP and rudimentary method-
ology to the historical archives.

Patient Evaluation

In order to improve surgical success, it is important to first analyze cases of surgical

failure. One major contributor to persistent symptoms after surgical therapy is the
failure of identifying comorbid sleep disorders. Approximately one third of patients
with OSA have another sleep disorder that may be causing or at least contributing
to the patient’s symptoms [5]. A patient whose excessive daytime sleepiness is
primarily related to restless legs syndrome, as opposed to the patient’s OSA, will
clearly have no chance of successful symptomatic improvement with airway
surgery. Therefore, a comprehensive sleep history and evaluation for other con-
founding sleep pathology is critical to managing OSA patients effectively.
Diagnostic failure can also take the form of inadequate examination of the airway
and identification of the specific anatomical concerns. The problem with sleep apnea
is not one of “stenosis” or “site of obstruction.” Instead the upper airway is a physi-
ologic tube with properties of size, shape, compliance, and length, best modeled in
the form of a Starling resistor [6, 7]. It is not simply the level of obstruction that
counts; but rather, the specific structure, anatomy, and pattern of obstruction
that drives proper surgical procedure selection. Just because a patient with clear
palatal obstruction undergoes a palatal procedure, does not necessarily ensure that
the patient’s palatal obstruction was adequately addressed. Successful surgical therapy
is critically dependent on knowledge of the airway anatomy and physiology.
A number of diagnostic tools are available to assist the surgeon in preoperative
upper airway evaluation and to guide surgical planning [8]. Radiographic techniques
include lateral cephalometric X-ray, computed tomography (CT) scan, and
10 Obstructive Sleep Apnea: Surgery 179

cine-magnetic resonance imaging (cine-MRI). Cephalometric X-rays are the most

commonly used radiographic tool. They are particularly useful for analyzing
craniofacial anatomy and preparing for skeletal surgery. The information is limited,
however, in that the images are usually obtained while the patient is awake and upright
and do not provide dynamic visualization of the soft tissue anatomy and airway
physiology. Sleep MRI is an emerging technology that addresses some of these
limitations although cost and machine noise effects on sleep are barriers to
widespread adoption of this tool.
Direct visualization techniques include head and neck physical examination,
flexible nasolaryngoscopy, and drug-induced sleep endoscopy (DISE). Physical
examination is essential to patient evaluation and generally quick and inexpensive
to perform. DISE allows for dynamic examination of the airway during conditions
that mimic the low airway muscle tone of sleep [9]. When performed under specific
conditions and guidelines, propofol-induced sleep correlates most closely with
deeper levels (stage N2) of NREM sleep and maintains a similar AHI as compared
to physiologic sleep [10]. Studies of sleep endoscopy have demonstrated validity,
test–retest reliability, and inter-rater reliability [11, 12]. Recent data suggests that
utilization of DISE can improve treatment outcomes with oral appliances [13–15].

Snoring

On the spectrum of sleep-related breathing disorders, non-apneic snoring is a very

common condition. Snoring is often the chief complaint of patients and subjectively
more important to most patients than daytime sleepiness, regardless of the AHI
[16]. Snoring has been shown to disrupt bed-partner sleep and have negative
impact on marital relationships. Further, treatment of snoring not only improves the
patient’s sleep but has also been documented to improve the bed-partner’s sleep,
with a reduction in the bed-partner’s arousal index and improvement in sleep
duration and efficiency [17]. In pediatric populations, primary snoring has been
directly linked to elevated nocturnal diastolic blood pressure, after controlling for
other clinical factors [18].
Recent evidence also suggests that vibratory trauma from snoring may cause
direct endothelial injury and may be an independent risk factor for carotid athero-
sclerosis [19]. Researchers in Australia have developed a rabbit model for evaluat-
ing the effects of snoring on the carotid artery. They have concluded that significant
vibrational energy is transmitted to the carotid arterial wall during snoring, and may
provide a link to carotid atherogenesis and cerebrovascular risk [20, 21].
Some patients with an AHI in the normal range, particularly younger patients,
may demonstrate flow limitation, snoring, and increased respiratory effort with a
subsequent clinically significant negative impact on their sleep. Many of these
patients with a true sleep-related breathing disorder are not offered positive pressure
or other forms of medical therapy because of the misdirected sole focus on the AHI
alone. Although hundreds of over-the-counter products are available to treat this
180 R.J. Soose and P.J. Strollo

condition, known as non-apneic snoring or upper airway resistance syndrome, most

do not work, and again potentially more effective medical therapy options such as
CPAP are typically either not covered by insurance and/or not tolerated by this
subset of patients [22].
In properly selected patients, surgical treatment options, often done under local
anesthesia in the outpatient office, can provide excellent results with minimal
discomfort, morbidity, and risk. Nasal surgery alone in patients with increased nasal
resistance and symptomatic nasal obstruction has been shown to improve snoring,
presumably by restoring laminar airflow entering the pharynx and subsequently
reducing palatal flutter. Tonsillectomy and/or adenoidectomy, particularly in pediatric
patients, can be an attractive first-line treatment option for non-apneic snoring in
patients with adenotonsillar hypertrophy. In about 80% of patients with non-apneic
snoring, the pathophysiology lies in a palatal flutter mechanism. In patients with
palatal flutter, without adenotonsillar hypertrophy or nasal obstruction, a variety of
office-based surgical procedures, such as injection snoreplasty, radiofrequency
treatment, or palatal implants can provide effective control of snoring and improve-
ment in subjective sleep quality and daytime sleepiness [23–25].

Nasal Surgery

Anatomy and Physiology

Most otolaryngologists have had patients return to the office after nasal surgery,
performed for other non-sleep-related sinonasal problems, only to report that their
sleep quality dramatically improved after their nasal surgery. Almost 500 years ago,
the Dutch physician, Lemnius [26], provided one of the first documented reports of
nasal obstruction and its negative impact on sleep. The literature is abundant with
data linking the nasal airway and sleep, although the exact relationship has been
rather elusive.
Knowledge of the nasal anatomy (i.e., internal and external nasal valve areas)
and the physiology (i.e., autonomic control of venous capacitance vessels) are
essential to proper evaluation of the nose as it relates to sleep-disordered breathing
(Fig. 10.1). The internal nasal valve, which is bordered by the anterior septum,
anterior tip of the inferior turbinate, and the caudal border of the upper lateral carti-
lage, is the area of highest nasal resistance. This is important for breathing during
sleep because nasal resistance accounts for more than half of the total upper airway
resistance. Airflow mechanics (Poiseuille’s law) dictate that very small changes in
cross-sectional radius (r) can exponentially affect airflow (Q): Q = DPpr4/8 mL.
Both structural and inflammatory mechanisms can contribute to increased nasal
resistance and subsequent negative impact on sleep (Tables 10.1 and 10.2). Therefore, a
wide variety of both medical and surgical management strategies are available depend-
ing on each patient’s specific pathophysiology. The coronal maxillofacial CT scan shown
illustrates a common example of multiple causes of nasal obstruction (Fig. 10.2).
10 Obstructive Sleep Apnea: Surgery 181

Fig. 10.1 Nasal anatomy: (a) Structural anatomy of the nasal septum (left) and lateral nasal wall
(right); (b) cross-sectional anatomy of the external nasal valve area; and (c) cross-sectional anat-
omy of the internal nasal valve area, which corresponds to the location of highest nasal airway
resistance. Courtesy of Springer images

Tonsillar hypertrophy has been shown to increase nasal resistance and contribute to
symptomatic nasal obstruction and mouthbreathing [27].

Allergic Rhinitis and Sleep

Sleep impairment is very common in patients with allergic rhinitis, chronic rhinosi-
nusitis, and nasal polyposis, and has a significant impact on disease-specific and
general health quality of life measures [28]. In fact, sleep disturbance is one of the
182 R.J. Soose and P.J. Strollo

Table 10.1 Medical/inflammatory causes of increased nasal resistance

Allergic rhinitis
Non-allergic rhinitis
• Vasomotor rhinitis
• Atrophic rhinitis
• Rhinitis medicamentosa
• Non-allergic rhinitis with eosinophilia syndrome (NARES)
• Medications (e.g., antihypertensives, aspirin, oral contraceptives)
• Infection (e.g., common cold, chronic rhinosinusitis)
• Hormonal (e.g., pregnancy, hypothyroidism)
• Autoimmune (e.g., lupus, Wegener’s, rheumatoid arthritis)
• Occupational (e.g., chemicals, paint fumes, chalk dust, saw dust, perfumes)
• Smoking

Table 10.2 Structural causes of increased nasal resistance

Common
• Deviated nasal septum
• Inferior turbinate hypertrophy
• Concha bullosa
• Nasal polyps
• Adenoid hypertrophy
• Tonsillar hypertrophy
• Narrow pyriform aperture/hard palate
Uncommon
• Inverting papilloma
• Neoplasm
• Foreign body
• Synechiae
• Meningocele
• Granulomatous disease

key factors in the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines that
distinguishes between mild and moderate–severe disease [29]. Furthermore, the
degree of sleep impairment is linearly related to the severity of their sinonasal disease
at the time, i.e., patients with predominant tree pollen allergy have noticeable wors-
ening in their sleep during the spring pollen season. In Craig’s survey of over 2,000
allergy patients, nasal congestion is the most common complaint and approximately
half report difficulty falling or staying asleep [28].
There is a circadian variation to nasal congestion with a predictable worsening
overnight in most patients. This physiology is likely multifactorial and attributable
to gravity effects of the dependent sleeping position and a decrease in serum cortisol
levels overnight. Inflammatory mediators associated with allergic rhinitis demon-
strate a circadian rhythm with progressive worsening overnight and peaking in the
early morning hours (average ~6:00 a.m.) [28].
10 Obstructive Sleep Apnea: Surgery 183

Fig. 10.2 Nasal obstruction:

A coronal maxillofacial CT
scan shows a deviated nasal
septum to the left (DNS),
inferior turbinate hypertrophy
(IT), and a right concha
bullosa (CB). This scan also
depicts inflammatory changes
in the maxillary (M) and
ethmoid (E) sinuses and
obstruction of the
osteomeatal complexes
(OMC), often seen with
chronic rhinosinusitis

Table 10.3 Pathophysiologic mechanisms of nasal obstruction and sleep-disordered breathing

• Decreased nasal receptor stimulation
• Increased negative inpiratory pressure in the pharynx
• Increased velocity and turbulence of airflow and palatal flutter
• Shift to oral breathing and posterior displacement of the mandible
• Skeletal changes (chronic)
° Maxillary hypoplasia
° Inferior displacement of the mandible
° Narrowing of dental arches
° Anterior crossbite
° Maxillary overjet
° Increased anterior facial height (elongated face)

Pathophysiology of Nasal Obstruction and Sleep Disturbance

A number of mechanisms have been proposed to explain how nasal obstruction

negatively impacts breathing during sleep (Table 10.3). In 1985, White et al. [30]
showed that abolishment of the nasal receptor reflexes with topical lidocaine con-
tributes to an increase in airway obstruction and depression of the central respira-
tory drive. Other studies confirm that nasal breathing, as opposed to oral breathing,
is associated with greater minute ventilation and an increase in pharyngeal muscle
activity [31, 32].
Rhesus monkey studies at UCSF in the 1970s elegantly showed that animals with
nasal occlusion developed severe craniofacial changes during growth (Table 10.3),
all of which have been associated with sleep-disordered breathing in adulthood
[33, 34]. It has been hypothesized that a vicious cycle evolves in some patients
where nocturnal breathing abnormalities cause unstable oral breathing and secondary
184 R.J. Soose and P.J. Strollo

Table 10.4 Surgical therapy options to treat nasal obstruction

• Septoplasty
• Inferior turbinate reduction
• Nasal valve procedures (e.g., spreader grafts, suspension
suture)
• Adenoidectomy
• Tonsillectomy
• Nasal polyp removal
• Concha bullosa resection
• Lysis of synechiae
• Rapid maxillary expansion

impaired craniofacial growth which then reinforces abnormal breathing. Multiple

human studies of nasal occlusion confirm the negative impact on sleep, demonstrating
sleep fragmentation, abnormal sleep architecture, and increased respiratory events
in patients with nasal obstruction [35–37]

Nasal Obstruction and Sleep-Disordered Breathing

A number of large population-based studies have analyzed the association of nasal

obstruction and subjective sleep measures, snoring, and sleep apnea. In the Wisconsin
cohort of almost 5,000 patients, nasal congestion was associated with an increased
risk of non-restorative sleep and daytime sleepiness [38]. Several large epidemio-
logic studies report that nasal congestion is an independent risk factor for snoring
[38–40]. Some studies have also shown that, across a large population, nasal obstruc-
tion is also an independent risk factor for OSA [39, 41].

Surgical Treatment of Nasal Obstruction

It is clear that nasal obstruction can have significant negative impact on both
subjective and objective sleep measures as well as on the risk of sleep-disordered
breathing. Until recently, it has been unclear what effect treatment of the nose has
on these parameters. The management approach to the patient generally involves
first identifying and medically treating allergic rhinitis or any other inflammatory
process that may be present. For structural anatomical problems, surgical therapy
can be very effective but the specific procedures indicated may vary from patient to
patient and depend on the specific anatomical problem. Although septoplasty and
inferior turbinate reduction are most commonly performed in adults, procedure
selection must be customized to each individual’s anatomical pattern of obstruction
(Table 10.4).
10 Obstructive Sleep Apnea: Surgery 185

An exhaustive description of the specific surgical techniques, pearls, and pitfalls,

is beyond the scope of this chapter. More important is an analysis of the results
obtained, as they relate to sleep-disordered breathing, by surgically lowering nasal
resistance. In 2008, Li et al. [42] showed that, for OSA patients with a deviated
nasal septum and symptomatic nasal obstruction, septoplasty lowered nasal resis-
tance, increased mean cross-sectional area, and significantly improved snoring as
measured by both the Snore Outcomes Survey and Spouse/Bed Partner Survey.
Similar improvement in nasal resistance and snoring was noted by Nakata et al. [27]
in 2007 after simple tonsillectomy in patients with 3–4+ tonsils.
Nakata et al. [43] also recently demonstrated that nasal surgery, in the setting of
nasal obstruction and sleep apnea, improves nasal resistance, sleep architecture, and
daytime sleepiness. In these patients, improvement in the ESS (10.6 → 4.5) with
nasal surgery is comparable to the improvement obtained with other forms of OSA
therapy, including positive pressure. In a prospective longitudinal cohort study of
patients with nasal obstruction and OSA, nasal surgery also significantly improved
both disease-specific and general health (SF-36) quality of life measures [44]. Even
in pediatric OSA populations, attention to nasal obstruction is important. Sleep
physicians at Stanford recently demonstrated that pediatric patients with enlarged
inferior turbinates often had both subjective and PSG evidence of persistent disease
after adenotonsillectomy alone [45]. These residual symptoms and AHI elevation
were subsequently improved further with the addition of radiofrequency turbinate
reduction.
Despite the evidence of the beneficial impact of lower nasal resistance on
sleep architecture, sleep efficiency, snoring, daytime sleepiness, and quality of life
measures, the importance of treating nasal obstruction has often been overlooked
because of its variable and sometimes negligible effect on the AHI. Across large
heterogeneous populations, lowering nasal resistance may have little effect on
the AHI, which makes sense since it is the pharynx, not the nose, where dynamic
airway collapse occurs. However, in selected OSA patients with a normal hypopha-
ryngeal airway, as demonstrated by cephalometrics or physical exam, a clinically
significant reduction in the AHI may be achieved. Patient cohorts in which nasal
surgery results in successful lowering of the AHI include: small tonsils, low modi-
fied Mallampati score, and a normal mandibular plane to hyoid (MP-H) distance
on cephalometry. Upper airway exam findings that are associated with a minimal
impact on the AHI with nasal surgery alone include: large tonsils, modified
Mallampati III/IV, and/or a low hyoid position [46–48].

Nasal Surgery and Improved Effectiveness of Medical

Therapy for OSA

Mounting evidence suggests that increased nasal resistance negatively impacts

success rates and tolerance of medical therapy devices, such as CPAP and oral
appliances, that are critically dependent upon regular usage to be effective.
186 R.J. Soose and P.J. Strollo

With logistic regression analysis, Suguira et al. [49] concluded that increased
nasal resistance was one of only two factors associated with non-acceptance of
CPAP. In patients with poor CPAP compliance and nasal obstruction, lowering nasal
resistance with surgical therapy has been shown to lower average CPAP pressures and
improve compliance [50]. Finally, high nasal resistance may negatively impact treat-
ment outcomes in OSA patients treated with mandibular advancement devices [51].

Oropharyngeal Surgery

History

Most physicians are familiar with the general concept of UPPP. Palatal obstruction
has been documented to be at least a contributing factor in most patients with OSA
and therefore palatal surgery plays a role in surgical therapy, particularly in those
patients who fail other forms of medical therapy. The specific role of palatal surgery,
however, has been poorly understood until recently. Some patients achieve excellent
results with significant symptomatic relief and a dramatic improvement in PSG
measures, while others have had minimal improvement or even worsening of their
apnea after traditional UPPP surgery.
Traditional UPPP was first described by Fujita in 1981, the same year that
CPAP was introduced [52]. Although not as much was known at the time about the
pathophysiology or cardiovascular sequelae of OSA, it represented a major treat-
ment advance since, prior to 1981, tonsillectomy and tracheotomy were the only
known effective surgical therapies. This ablative procedure essentially involves
resection of tissue (mucosa, muscle, and glandular tissue) by removing the tonsils,
uvula, and part of the soft palate.
Until recently, this particular procedure was largely unchanged and surgical
series resulted in mediocre results at best, particularly when used as a sole procedure.
In 1996, Sher et al. [2] attempted to summarize UPPP efficacy with a review of 37
papers and approximately 500 patients who underwent surgical therapy for OSA.
These surgical series were hampered by poorly defined inclusion/selection
criteria, variable surgical technique, and inconsistent follow-up. Sher defined surgical
“success” as a postoperative respiratory disturbance index (RDI) <20 with at least a
50% reduction from baseline, or an apnea index (AI) <10 with at least a 50% reduc-
tion from baseline. Summarizing the data from these 500+ patients, a 41% “success”
rate was reported. Although similar to long-term acceptable compliance rates with
other forms of medical therapy, the overall results were unimpressive.
In many studies that followed, the subsequent goal was then to determine which
patient factors predicted success and to preselect those patients for traditional UPPP
who would fall into that 41%, rather than modifying and improving the surgery
itself. This restricted approach, with essentially one treatment option, is problematic
in that many patients are then left untreated if they are not deemed good candidates.
Further, most patients have multilevel obstruction that requires more comprehensive
10 Obstructive Sleep Apnea: Surgery 187

airway reconstruction rather than one isolated procedure. For the most part, the
patients select the surgeon; the surgeon does not select the patients. Patients who
fail other forms of medical therapy for sleep apnea present to the surgeon with hope
to improve their symptoms, to improve their quality of life, and to improve their
cardiovascular and general health. These patients seek additional treatment options,
not simply to see if they are a candidate for one particular procedure.

A Paradigm Shift

A major paradigm shift is underway with the fundamental goal of improved morbidity
and effectiveness with more anatomically and physiologically sound reconstructive,
rather than ablative, surgical procedures. As such, more recent advances have been
directed toward properly phenotyping the airway and the specific anatomical pattern
of obstruction, and therefore allowing customization of a surgical treatment algo-
rithm for each patient, which often includes a palatal procedure.
Multiple prior studies of cases of UPPP failure have arrived at strikingly similar,
and potentially shocking, conclusions. Whether using imaging, manometry, or videoen-
doscopic techniques, approximately 84% of patients who have persistent disease
after traditional UPPP have been shown to still have significant obstruction at the
retropalatal portion of the airway [53]. In 1998, Langin aimed to evaluate the impact
of UPPP on upper airway anatomy by posing the questions: (1) does traditional
UPPP actually enlarge the oropharyngeal airway, and (2) could the outcome of
UPPP be explained in terms of the morphological modifications produced by the
surgery? Those patients who responded to palatal surgery with a successful
reduction in the AHI (13 → 4) had a significant increase in the cross-sectional
area at the level of the oropharynx. In contrast, the “non-responders” (AHI 14 → 25)
had no change in the cross-sectional area, or in some cases even a smaller retropalatal
airway, after palatal surgery [54].
These findings reinforce the idea that is not simply the level of obstruction
that predicts surgical success; rather, it is the specific pattern of obstruction, proper
selection of the specific type of palatal surgery, and proper execution of the surgical
technique that determine results. In other words, just because a patient with palatal
airway obstruction undergoes a palatal procedure does not mean that the palatal
airway was adequately enlarged or stabilized.
Effectiveness is not the only factor driving the decision for surgery. Perioperative
morbidity, side effects, and risk are just as important. Tracheotomy and bimaxillary
advancement are quite effective but the associated morbidity precludes use in most
patients. Serious perioperative complications of palatal surgery are uncommon
(~1%) even in a large VA patient population with a high incidence of smoking [55].
Nevertheless, other side effects, such as globus sensation, mucous feeling, dry
throat, and change in voice/swallowing, may be relatively common and underreported
with traditional UPPP. These side effects can be quite bothersome to the patient and
potentially irreversible.
188 R.J. Soose and P.J. Strollo

The Importance of Uvular Preservation

These benign, but often underreported, side effects may be significantly lessened by
newer techniques and instrumentation designed to preserve mucosa, limit collateral
thermal damage, and improve postoperative medical therapy. One of the most
important changes, however, that may dramatically reduce morbidity and improve
postoperative recovery and function is the preservation of the uvula. While tradi-
tional UPPP techniques involve resection of the entire structure of the uvula, current
understanding of pharyngeal physiology suggests that the uvula is an important
physiologic structure, rather than part of the airway problem in sleep apnea.
The uvular submucosa has a uniquely extensive immune cell population, primarily
mast cells, that is important for the immunologic induction of mucosal tolerance to
inhaled and ingested antigens [56]. The uvula has one of the highest concentrations
of type II, fast-twitch, muscle fibers in the human body – essential for the quick
coordinated movements of speech and swallowing function. Its glandular area also
comprises highest concentration of serous glands (as opposed to mucous glands) in
the oral cavity and oropharynx. The storage ducts are capable of quickly secreting,
via muscle contraction, large volumes of serous fluid [57]. With videoendoscopic
techniques, Back et al. [58] demonstrated that the uvula plays an essential role in
basting the posterior pharyngeal wall with thin serous saliva. These findings likely
explain the local pharyngeal side effects that occur in many patients undergoing
traditional UPPP and in part serve as the basis for the development of newer, less
morbid, and more effective palatal surgical procedures.

Palatal Anatomy and Examination

Proper procedure selection and execution are integrally dependent upon knowl-
edge of the anatomy and physiology of the upper airway. Terms such as a “crowded
airway” and even the Fujita classification are not sufficiently descriptive or useful
in determining procedure selection and predicting success. The pharynx is
best conceptualized anatomically as a muscle buttress system involving the
palatopharyngeus and levator palatinus muscles, as well as the tensor palatini,
palatoglossus, salpingopharyngeus, and uvular muscles. Physical examination of
the oropharynx should include description of the palate/tongue relationship
(Modified Mallampati or Friedman Tongue Position), tonsil size, lateral wall
component (palatopharyngeus muscle), anterior/posterior depth, and vertical
shape of the palate (Fig. 10.3).
Although many modifications and advances in palatal surgery have been reported,
two procedures seem to be uniquely suited to improved effectiveness, via more
anatomically sound technique, and reduced morbidity, via mucosal/uvula preserva-
tion: (1) expansion sphincter pharyngoplasty (ESP), and (2) transpalatal advancement
pharyngoplasty. A more in-depth discussion of all available palatal procedures for
OSA is beyond the scope and extent of this chapter. For further analysis of additional
10 Obstructive Sleep Apnea: Surgery 189

Fig. 10.3 Examination of the oropharynx: Examples of the methods used to stage and phenotype
the oropharyngeal airway include (a) tonsil size, and (b) modified Mallampati or Friedman tongue/
palate position. Reproduced from [72]
190 R.J. Soose and P.J. Strollo

Fig. 10.4 Expansion

sphincter pharyngoplasty
(ESP): Illustration of basic
surgical principles of ESP.
(a) After tonsillectomy, the
palatopharyngeus muscle
(PP) is isolated from the
posterior tonsillar pillar,
transected, rotated, and
suspended submucosally.
(b) The resultant effect is an
anterior, superior, and lateral
suspension (arrows) of the
palatal insertion of the
palatopharyngeus muscle and
subsequent expansion of the
lateral retropalatal ports with
maximal mucosal
preservation. The uvula can
be shortened or contoured as
needed but the uvular muscle
and structure is generally left
intact. Reproduced with
permission from Elsevier
Health Sciences [60]

palatal techniques, the reader is referred to Michael Friedman’s surgical text,

Snoring and Obstructive Sleep Apnea [59].

Surgical Techniques

Expansion Sphincter Pharyngoplasty

Many patients with retropalatal obstruction have a more obliquely oriented palate
with a circumferential pattern of collapse and hypertrophied lateral pharyngeal
walls. The anterior/posterior space between the hard palate and posterior pharyn-
geal wall is often open. Originally described by Woodson and Pang in 2007, ESP is
uniquely suited to address this anatomy (Fig. 10.4).
10 Obstructive Sleep Apnea: Surgery 191

Fig. 10.5 ESP:

Intraoperative photographs of
ESP. (a) The tonsils have
been removed bilaterally with
maximal mucosal
preservation. ESP has been
completed on the patient’s
right side (R) with a
noticeable enlargement of the
right retropalatal airway
(ellipse), as compared to the
unoperated left side ( L ).
( b ) Final intraoperative
appearance after completion
of ESP on both sides and
contouring of the uvula. The
anchor points of the
palatopharyngeus suspension
near the hamulus can be seen
in the upper right and left
sides of the photograph. Note
the lateral expansion of the
right retropalatal space with
essentially no resection of
tissue, minimal mucosal
trauma, and preservation of
the uvular structure

If present, the tonsils are first removed with maximal mucosal preservation. The
palatopharyngeus muscles, which primarily account for the enlarged and medialized
lateral pharyngeal walls, are isolated and suspended in an anterior, superior, and
lateral vector towards the hamulus. The resultant effect is a dramatic opening of the
retropalatal space in a lateral dimension, again with minimal to no resection of
mucosa or other soft tissue. Additional contouring of the uvula and velum can be
combined with the expansion pharyngoplasty; however, the bulk of the uvular structure
and function is preserved (Fig. 10.5). The superior effectiveness of ESP, compared
to traditional UPPP, has been established in a prospective randomized controlled
trial (Table 10.5) [60].

Transpalatal Advancement

Transpalatal advancement surgery is based on the concept that some patients have
palatal anatomy that is more representative of maxillary deficiency/retrusion and
192 R.J. Soose and P.J. Strollo

Table 10.5 Results of a randomized controlled trial

comparing AHI reduction with expansion sphincter phar-
yngoplasty (ESP) vs. traditional uvulopalatopharyngo-
plasty (UPPP)
ESP UPPP
Preoperative AHI 44.2 38.1
Postoperative AHI 12.0 19.6
P value 0.005 0.05
Mean change in AHI 32.3 18.5
Success ratea (%) 78.2 45.5
a
AHI reduction >50% and AHI <15
Adapted with permission from Sage Publications [60]

narrowing of the space between the posterior edge of the hard palate and the posterior
pharyngeal wall. These patients generally have a more vertically oriented, low-lying,
elongated soft palate, with a more anterior–posterior pattern of collapse (Fig. 10.6).
Transpalatal advancement essentially involves an osteotomy that removes the
posterior portion of the hard palate and advances the soft palate forward (Fig. 10.7).
This procedure aims to achieve the enlargement of the retropalatal space similar to
that obtained with a traditional maxillary advancement surgery, without the associ-
ated morbidity and potential cosmetic/dental changes.
Multiple studies have shown superior effectiveness compared to traditional
UPPP with clinically significant improvement in the AHI (52 → 12), increase in the
retropalatal airspace (+321%), and reduction in the critical closing pressure (−8.5 cm
H2O) [61–63]. In a recent retrospective comparison between TPA and UPPP, after
adjusting for other clinical factors, the odds ratio of surgical “success” was 5.8 with
TPA compared to UPPP [64].

Hypopharyngeal Surgery

Background

In the past, hypopharygneal surgery was often relegated to patients with moderate–
severe disease only or to those who first failed traditional UPPP. Technological
advances have improved preoperative evaluation of the hypopharynx as well as
intraoperative surgical exposure and postoperative recovery. Regardless of the
sleep apnea severity, hypopharyngeal obstruction plays a role in most patients with
OSA. Multilevel (nasal, oropharyngeal, and hypopharyngeal) obstruction is common
in adult OSA patients, even in patients with mild disease [65]. In many patients who
have failed medical therapy, surgical planning must include treatment of hypopha-
ryngeal obstruction to improve treatment outcomes.
10 Obstructive Sleep Apnea: Surgery 193

Fig. 10.6 Transpalatal advancement: Mid-sagittal depiction of the concept of transpalatal advance-
ment surgery for patients with maxillary deficiency and a more vertically oriented palate. A portion
of the distal hard palate is removed (a) with subsequent advancement (b) of the soft palate and
increased cross-sectional area of the retropalatal airspace. Reproduced with permission from
Elsevier Health Sciences [73]

Anatomy

No single surgical procedure is warranted in all patients. Rather, just as in palatal

surgery, proper procedure selection and execution must be dictated by each patient’s
anatomical pattern of obstruction. A variety of components can contribute to hypo-
pharyngeal airway collapse including the lingual tonsils (Fig. 10.8), tongue base,
194 R.J. Soose and P.J. Strollo

Fig. 10.7 Transpalatal advancement: Diagram of the steps involved in transpalatal advancement
surgery. (a) Depiction of the planned palatal incision (solid lines), junction of the hard and soft
palate (dashed line), and location of the greater palatine foramina (dots). (b) Flap elevation and
exposure of the hard palate. (c) Site of planned osteotomy (dashed line) and drill holes (solid cir-
cles). (d) After completion of the osteotomy and separation from the posterior nasal septum.
(e) Sutures are placed through the drill hole anchors and around the posterior osteotomy and tensor
aponeurosis, advancing the soft palate forward. (f) Closure of the incision and completion of the
procedure. Note the preservation of the uvula and soft palate mucosa. Reproduced with permission
from Elsevier Health Sciences [73]

epiglottis, and lateral pharyngeal walls. Evaluation of the specific pattern of collapse
may be best achieved at this point in time with DISE as this provides direct visualization
of the hypopharynx, in the supine position and in a dynamic state that mimics the
lower genioglossus muscle tone of NREM sleep. Other options for the diagnostic
assessment of hypopharyngeal obstruction include awake physical exam, supine
awake nasolaryngoscopy, cephalometrics, and MRI.
The Moore classification (Fig. 10.9) of tongue base anatomy currently provides
the best description of the anatomy and therefore assists in proper procedure
selection [66]. A wide variety of both skeletal and soft-tissue reconstructive surgical
procedures are available to address the hypopharynx, which in conjunction with the
large variations in patients’ anatomy, contributes to the difficulty in studying
the effectiveness and obtaining clear data on these procedures. Many of the hypo-
pharyngeal surgical techniques have been described in smaller case series and are
confounded by the inclusion of other airway procedures.
10 Obstructive Sleep Apnea: Surgery 195

Fig. 10.8 Lingual tonsil hypertrophy: Sagittal magnetic resonance imaging (MRI) depicting
hypertrophy (arrows) of the lingual tonsils and narrowing of the hypopharyngeal airway

Hypopharyngeal Surgical Techniques

Newer surgical techniques are rapidly evolving and resulting in improved effectiveness
and much lower morbidity compared to past procedures. Volumetric reduction of
the tongue base (midline glossectomy) with plasma technology appears to be a
promising tool for effective enlargement of the hypopharyngeal airway, with relatively
minimal discomfort, quick recovery to normal diet, and excellent results [67]. This
technology now can be used to safely and effectively remove enlarged lingual
tonsils as well, which in the past was often considered a procedure with difficult
exposure and high morbidity [67].
Although radiofrequency reduction of the tongue base has been associated with
subjective and objective sleep apnea improvement in a randomized clinical trial,
histologic analysis suggests that the actual reduction in the tongue size is relatively
small with radiofrequency reduction compared to more effective midline glossectomy
techniques [68]. Nashi et al. [69] have demonstrated that significant fat deposition
occurs in the tongue base as BMI increases. This finding again supports the need for
procedures with substantial volumetric reduction and/or advancement of the tongue
base as opposed to radiofrequency ablation alone.
One innovative solution on the horizon, that may address hypopharyngeal
obstruction in through more physiologically sound mechanism, involves the stimulation
196 R.J. Soose and P.J. Strollo

Fig. 10.9 Moore tongue base

classification: Sagittal
depiction of different patterns
of hypopharyngeal
obstruction. Type A: high
tongue base which
predominantly reflects lingual
tonsil hypertrophy. Type B1:
high tongue base with
retroepiglottic narrowing.
Type B2: diffuse tongue base
narrowing. Type C: primary
retroepiglottic narrowing.
Reproduced with permission
from Elsevier Health
Sciences [66]

Table 10.6 Examples of minimally invasive surgical options

for the specific treatment of hypopharyngeal obstruction
• Radiofrequency tongue base reduction
• Transoral submucosal endoscopic-assisted
glossectomy
• Coblation lingual tonsillectomy
• Tongue base stabilization with suture suspension
• Genioglossus advancement
• Hyoid suspension

of the hypoglossal nerve through an implantable pacing device that coordinates

with the patient’s respiratory pattern [70]. Again, detailed discussion of the specific
operative techniques and perioperative concerns is beyond the scope of this chapter
and is available in Friedman’s surgical text and atlas [59]. A sample list of hypopha-
ryngeal surgical options is presented in Table 10.6.

Maxillomandibular Advancement Surgery

Maxillomandibular advancement (MMA) commonly consists of a LeFort I maxillary

osteotomy combined with sagittal split osteotomies of the mandible. The superior
effectiveness of maxillomandibular skeletal advancement surgery has been fairly
well established with rates of clinically significant improvement in subjective and
objective OSA measures often exceeding 90% [71]. MMA succeeds because of
10 Obstructive Sleep Apnea: Surgery 197

its sound anatomical principles, as referenced earlier in the oropharyngeal surgery

section, of reconstructive (as opposed to excisional/ablational) enlargement of the
airway on multiple levels. Nevertheless, the invasiveness, prolonged recovery,
cosmetic changes, paresthesias, potential dental injury or malocclusion, and overall
high morbidity preclude its use in most OSA patients, particularly those with mild
to moderate disease.
The decision for surgery in any patient depends not only on effectiveness of the
procedure but also on perioperative risk and morbidity. Tracheotomy is also an extremely
effective surgical therapy for sleep apnea but is declined by the vast majority of
patients because of the psychosocial implications and potential medical complications.
MMA may be a reasonable treatment option for patients with severe persistent OSA
despite prior medical and surgical failure or for patients with maxillomandibular
deficiency or other craniofacial abnormalities; however, for the average OSA patient
presented with this option, the morbidity and potential complications far outweigh
the potential benefits.

Conclusion

Numerous medical and surgical options exist for the treatment of sleep-disordered
breathing. Although large numbers of patients are successfully managed with nasal
CPAP, the most common form of medical therapy, many patients still fail to achieve
adequate treatment over the long term and, clearly, there is a enormous demand for
improved treatment options.
Surgical therapy does not play just one role in the management of OSA and does
not consist of a sole treatment; rather, the goals of surgery depend on each patient’s
unique anatomy and clinical context. Surgery should be aimed at prevention of
cardiovascular risk, symptom resolution, quality of life improvement, reduction of disease
severity, or an adjunctive treatment to improve outcomes with other forms of medical
therapy.
Successful surgical therapy is critically dependent on accurate diagnosis, skillful
knowledge and examination of the upper airway anatomy, proper procedure selec-
tion, and proficient technical application. A major paradigm shift is underway to
(1) properly phenotype each patient’s multifactorial pattern of upper airway obstruc-
tion, and (2) customize a multilevel treatment plan with effective, low morbidity,
reconstructive techniques, rather than the “sole site” excisional model commonly used
over the past few decades.

Summary of Keypoints

• Airway reconstructive surgery plays a key role in the management of many

patients with OSA and has been demonstrated to successfully treat sleep-related
symptoms as well as long-term disease morbidity.
198 R.J. Soose and P.J. Strollo

• Evaluation of the effectiveness of surgical therapy is often complicated by the

wide variety of procedures and different surgical techniques available, in addition
to the ethical and practical concerns with instituting randomized controlled
sham-procedure studies.
• Effective surgical therapy requires a systematic algorithm that addresses the entire
upper airway, rather than one specific procedure or anatomical site. Successful
management demands comprehensive knowledge of upper airway anatomy
and physiology as well as the proper patient selection, procedure selection, and
technique execution.
• In patients who fail medical therapy options or in some patients with particular
anatomical features such as adenotonsillar hypertrophy, surgery may be employed
as sole or primary therapy. The goals of sleep surgery, however, vary from patient
to patient and can include reduction of cardiovascular risk, symptom resolution,
quality of life improvement, reduction of disease severity.
• Surgical therapy also may be used as an adjunctive treatment to improve compli-
ance and outcomes with other forms of medical therapy.
• Current state-of-the-art surgical therapy is characterized by (1) properly pheno-
typing each patient’s unique anatomical pattern of upper airway obstruction,
including the use of sleep endoscopy, and (2) customizing a multilevel treatment
plan with effective, low-morbidity, reconstructive techniques, rather than the
“sole site” excisional model commonly used over the past few decades.

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Chapter 11
Sleep and Lung Disease

Charles W. Atwood, Jr.

Keywords Hypoventilation • Neuromuscular disease • Obesity-hypoventilation

syndrome • Chronic obstructive pulmonary disease • Kyphoscoliosis

Introduction

Sleep disturbances are common in many respiratory disorders, including chronic

obstructive pulmonary disease (COPD), asthma, and restrictive lung disease. Sleep
is, in many ways, a time of vulnerability in respiratory illness. Changes in upper
airway resistance and, at times, lower airway resistance, may exacerbate underlying
pulmonary conditions. Sleep is also a time when hypoxemia may worsen, and this
may impose its own associated health hazards. Since COPD and asthma are very
common conditions, the burden of sleep-related physiological stress leads to a
significant burden in terms of the number of people affected. Sleep in patients with
less common lung diseases, such as restrictive disorders and obesity-hypoventilation
syndrome, show different patterns of physiological abnormalities during sleep. In
this chapter we will explore of the intersection between sleep and these important
pulmonary medicine conditions.

Sleep and COPD

COPD is a common condition affecting approximately 14 million Americans [1].

COPD is commonly subdivided into chronic bronchitis and emphysema. Clinically,
most patients have elements of each of these conditions in their day-to-day clinical

C.W. Atwood, Jr. (*)

Sleep Disorders Program, Pulmonary and Sleep Section, VA Pittsburgh Healthcare System,
University Drive C, Pittsburgh, PA, 15240, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 203
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_11,
© Springer Science+Business Media, LLC 2012
204 C.W. Atwood, Jr.

Fig. 11.1 An example of rapid eye movement (REM) sleep-related hypoventilation in a patient
with chronic obstructive pulmonary disease (COPD). The red horizontal bars indicate the periods
of desaturation. The top signal is heart rate. The bottom signal is oximetry. The black horizontal
bar at the Y axis next to the heart rate indicates 90 bpm. The horizontal bar at the Y axis next to the
oximetry channel indicates the 90% saturation mark. The patient experiences three periods of
desaturation corresponding to the times he enters REM sleep

life with COPD. COPD experts tend to favor splitting chronic bronchitis and
emphysema into relatively distinct syndromes, or phenotypes, as a way of under-
standing the pathophysiology of these two forms of chronic airflow obstruction. It is
not clear whether this distinction is important at the individual patient level [2].
Treatment options tend to be similar regardless of the relative importance of the two
forms of airflow obstruction in any one patient. Likewise, the differences between
chronic bronchitis and emphysema do not seem crucial to understanding the inter-
action between sleep and airflow obstruction.
When the patient with COPD falls asleep, there is a rapid decrease in alveolar
ventilation as the patient enters stages N1 and N2 sleep (the lighter stages of non-REM
sleep). Depending on the severity of the lung disease, the patient may experience
hypoxemia, which may exceed the magnitude of exercise-related hypoxemia.
Sleep-associated hypoxemia in patients with COPD is due to a combination of
sleep-induced hypoventilation and increased upper airway resistance [3].

Hypoventilation

Minute ventilation falls during all stages of sleep compared with wakefulness. This
is a normal part of sleep physiology. Patients with significant lung disease, and who
have gas transfer abnormalities at baseline, experience a greater degree of hypox-
emia because of the combined effect of lung disease and hypoventilation. NREM
sleep is associated with moderate hypoventilation, perhaps as much as a 20%
decrease in alveolar ventilation from baseline levels wakefulness level. However,
during rapid eye movement (REM) sleep, alveolar ventilation falls by as much as
40% [3] (Fig. 11.1). This is due to the skeletal muscle atonia, a physiological feature
11 Sleep and Lung Disease 205

unique to REM sleep. The diaphragm is among a few muscles that do not demonstrate
active inhibition during REM sleep. However, accessory muscles of respiration are
inhibited. Since many patients with advanced COPD use accessory muscles for ven-
tilation, the loss in total ventilatory effort during REM sleep can be significant.
Specifically, skeletal muscle atonia leads to a decrease in functional residual capacity
with ensuring atelectasis, ventilation-perfusion mismaching, increased shuntfrac-
tion, and subsequent hypoxemia [4].
Phasic REM is the most vulnerable point in REM sleep for hypoventilation, as
muscle paralysis extends even to the diaphragm. Transient episodes of diaphrag-
matic paralysis occur with phasic bursts of REMs [5]. Accordingly, hypoventilation
in vulnerable patients is most pronounced, even on a routine polysomnogram, during
physic REM sleep.
Another contributor to hypoxemia during sleep in patients with COPD is
increased upper airway resistance [6]. During non-REM sleep there may be an
increased respiratory drive despite the fact that the overall degree of ventilation
decreases. Increased respiratory drive is more than counterbalanced by upper airway
resistance, which leads to the net effect of a decrease in ventilation by a moderate
small to moderate amount.
The final mechanism contributing to COPD-related hypoxemia is the relative
disadvantaged flat position of the diaphragm in advanced COPD. This may explain
why nocturnal hypoxemia associated with COPD may be worse than the hypoxemia
associated with other forms of chronic lung disease that do not affect the position of
the diaphragm [7].

Measurement of Hypoventilation and Respiratory Dysfunction

It is difficult to assess individual mechanisms of hypoxemia during sleep, given the

difficulty in assessing ventilation perfusion matching noninvasively [8]. A chief
reason for the difficulty in making this measurement is the highly variable breathing
rate and tidal volume during REM sleep. Likewise, lung perfusion is affected by the
recumbent state during sleep where blood follows gravity and be directed to the
posterior lungs. Ventilation tends to be more concentrated in the anterior lung.
Depending on the location of emphysema in a given patient, the degree of increased
lower airway resistance from airway involvement from COPD, and other factors,
such as obesity, ventilation and perfusion relationships in COPD are variable,
dynamic, and difficult to measure.

Clinical Consequences of Sleep Hypoxemia in COPD

Sleep hypoxemia in COPD may have several important effects on the health of the
patient. There is compelling evidence that patients with COPD and hypoxemia have
increased pulmonary artery pressures associated with the lowering of the PaO2
206 C.W. Atwood, Jr.

during sleep. This may lead to fixed pulmonary artery hypertension and may
subsequent cor pulmonale [9]. One older study showed that the pulmonary arterial
pressure rose from 37 to 55 mmHg during REM sleep while the average PaO2 fell
to a low of 43 mmHg [10]. Animal models have shown that chronic hypoxemia for
2 h/day for 4 weeks can significantly increase right ventricular mass [11]. There are
no parallel human data; however, it seems likely that chronic hypoxemia has a similar
deleterious effect on the human myocardium.
Erythrocyte expansion is another consequence of chronic nocturnal hypoxemia.
Nocturnal desaturation leads to increased erythropoiesis and expansion of the red
cell mass. Morning erythropoietin levels are increased in some patients with COPD.
Erythropoietin, however, does not appear to be stimulated until oxygen saturation
falls to around 60% at night. It is likely there is a genetic predisposition to suscepti-
bility to hypoxemia and increased erythropoiesis since not all COPD patients with
similar degrees of nocturnal hypoxemia exhibit the same degree of erythropoiesis.
Poor sleep quality is a common complaint among patients with COPD. Sleep
quality defined both subjectively (questionnaires) and objectively (variables on
sleep studies) have been shown to be adversely affected. Arousals and sleep frag-
mentation are greater in hypoxemic COPD patients compared to those with
normoxia [12]. However, poor sleep quality cannot be attributed solely to hypoxemia
as patients with severe lung disease may have abnormal lung mechanics and report
more dyspnea. Interestingly, excessive daytime sleepiness is not a frequent complaint,
despite poor sleep quality.
The most serious acute complication of COPD with nocturnal hypoxemia is car-
diac arrhythmias. The relationship between ventricular ectopy severity or frequency
and nocturnal oxygen saturation is not very strong [13]. However, this may be a critical
problem in patients with concomitant COPD and cardiac disease and may explain, at
least partially, why heart disease is the leading cause of death in people with COPD.

Diagnosis of Nocturnal Hypoxemia in COPD

The diagnosis of nocturnal hypoxemia and COPD requires an overnight oximetry

recording, which can be performed easily and inexpensively in the patient’s home.
For some patients it may be appropriate to request an overnight study in a specialized
sleep laboratory. Polysomnography may be of value in such patients if obstructive
sleep apnea (OSA) or another sleep disorder are suspected. For routine purposes,
however, overnight oximetry is the appropriate first test.

Treatment of Nocturnal Hypoxemia

The primary treatment of nocturnal hypoxemia is supplemental oxygen [12, 14].

Nocturnal oxygen therapy is a straightforward therapeutic modality to prescribe.
There is good evidence to support its use for improvement of quality of life [12, 14].
11 Sleep and Lung Disease 207

Guidelines that govern its use in the United States are available. The most commonly
used set of guidelines are those of the Centers for Medicare and Medicaid Services
(CMS). These guidelines state that if nocturnal hypoxemia is observed with oxygen
saturation less than 88% for 5 min, supplemental oxygen may be prescribed.
Supplemental oxygen may be prescribed if the oxygen saturation is 89% and there
is clinical evidence of cor pulmonale, pulmonary hypertension, or erythocythemia.
Despite having guidelines governing supplemental oxygen use, the evidence for
providing oxygen therapy only during sleep is quite weak. There is extensive litera-
ture documenting benefits of oxygen to daytime hypoxemic COPD patients but this
does not extend to prescribing oxygen for isolated nocturnal desaturation. Despite
this lack of evidence, oxygen therapy for isolated nocturnal hypoxemia is com-
monly used. There are a number of unsettled questions about the treatment of
nocturnal hypoxemia with supplemental oxygen. First, it is not known whether
supplemental oxygen should be titrated during sleep or set at a fixed flow rate, with
the expectation that any reduction in the burden of sleep-related hypoxemia would
be beneficial. Titrating oxygen during sleep requires multiple nocturnal pulse oximetry
tests, which would add cost to the patient’s care.
Second, most practitioners do not routinely assess nocturnal hypoxemia in
patients with COPD who are prescribed daytime oxygen. Rather, either they may
continue the same liter flow during wakefulness during sleep or they may increase
the liter flow by an arbitrary amount, such as 1 L/min, during sleep. One study
demonstrated a reasonably linear relationship between daytime oxygenation and
nocturnal oxygenation in patients with COPD [15], making it feasible to estimate if
a patient would likely need nocturnal oxygen if their diurnal oxygen status were
known. The authors concluded that measurement of nocturnal oxygenation did not
add meaningful information to the assessment of daytime oxygen evaluation.

Medications

Several medications have been studied for their potential beneficial effect on
reducing nocturnal hypoxemia. Almitrine is a respiratory stimulant that is available
in Europe but not in the United States [16]; it may have a positive effect on ventilation
and perfusion relationship. However, its side effects outweigh its putative clinical
benefits. Older studies have examined the use of protriptyline, a tricyclic antidepres-
sant with strong anticholinergic properties (and thus REM sleep suppressing
properties) in the treatment of nocturnal hypoxemia with some showing benefit
[17]. Protriptyline may improve nocturnal oxygenation by decreasing REM sleep
and associated hypoventilation. However, it is not used, nor approved, for this indi-
cation, given its substantial side-effect profile. Finally, Medroxyprogesterone is a
respiratory stimulant, which, theoretically, may decrease nocturnal hypoxemia.
However, one double-blind placebo control trial showed no significant change in the
nadir of oxygen saturation in a study of COPD patients who were taking the
medication [18].
208 C.W. Atwood, Jr.

Alleviation of airflow obstruction is also expected to improve nocturnal

oxygenation. Inhaled bronchodilators, such as beta agonists and anticholinergic
bronchodilators may improve airway tone during sleep and one study has
demonstrated improvements in sleep quality. Similarly, theophylline may improve
nocturnal oxygen saturation through similar mechanisms. Nevertheless, beta
agonists and theophylline may disrupt sleep.
In summary, there are no effective pharmacological agents that prevent or miti-
gate nocturnal hypoxemia in patients with COPD.

Noninvasive Positive Pressure Ventilation

Some patients may benefit from nocturnal intermittent positive pressure ventilation
(NIPPV). This therapeutic technique was developed for patients with neuromuscular
or chest wall disorders but has been extended to patients with severe COPD [19,
20]. The literature for this application is mixed, as many patients are unable to tolerate
NIPPV. However, patients who tolerate NIPPV experience improvement in arterial
blood gases and quality of life, and reduced healthcare expenditures.

COPD and Obstructive Sleep Apnea: The Overlap Syndrome

Both COPD and OSA are common conditions with a similar prevalence in the
United States and most industrialized countries. Thus, some patients will have both
conditions. The coincidence of OSA and COPD is called the “overlap syndrome”
[21]. Patients with COPD should be asked about symptoms of OSA but routine testing
for this condition without clinical suspicion is not recommended. Patients with the
overlap syndrome may be at increase risk of more serious complications including cor
pulmonale, chronic peripheral edema that may lead to venous stasis and severely
impaired quality of life [21, 22]. Based on analyses from an ongoing large epide-
miological study examining cardiopulmonary aspects of sleep apnea, COPD, and
OSA do not have a common factor such that one modifies the other [23].

Sleep and Asthma

Asthma is a common disorder characterized by intermittent episodes of bronchoc-

onstriction, dyspnea, wheezing, and chest tightness. The pathogenesis of asthma is
airway narrowing due to edema and airway smooth muscle constriction. Airway
caliber, inflammatory cell influx, and likely other related aspects of asthma patho-
genesis have a well-defined circadian rhythm [24]. The sleep state is a major
synchronizing factor for airway narrowing although sleep deprivation studies
demonstrate airway narrowing despite the lack of sleep [24]. Mechanisms of airway
11 Sleep and Lung Disease 209

narrowing related to circadian timing or phase are not well understood but it is
likely that factors such as the presence of specific allergens, airway cooling, altera-
tions in mucus ciliary clearance and then pathological conditions, such as gastroe-
sophageal reflux, may contribute to bronchial hyperreactivity. Sleep stages per se
have not been shown to be significant factors in airway narrowing [25].
Other mechanisms which may influence asthmatic airway at night include auto-
nomic function and circadian variation of certain hormones and catecholamines
[26]. Cortisol contributes a modest amount to airway tone in normal individuals as
well as asthmatics [27]. Circadian timing-related airway inflammation has been
found in some but not all studies [28, 29]. The differences are likely due to incon-
sistencies in methodologies examining this question. Positive studies of airway
inflammation focusing on circadian factors have found increases in inflammatory
cells and bronchoalveolar lavage specimens at 4 a.m. compared to 4 p.m. [28, 30].
Similarly, pulmonary function tests such as FEV1 show a nadir in the early morning
hours compared to the afternoon hours. The mechanisms linking circadian rhythm
biology and airway inflammation remain uncertain.

Sleep Disturbances in Nocturnal Asthma

Sleep disturbance is a common complaint of asthma patients who experience a wors-

ening of their asthma at night. Nocturnal asthma symptoms may lead to worsening
of daytime performance, including impaired daytime cognitive function, and the
ability to perform at work and at school. Some patients may also develop nocturnal
hypoxemia; however, the degree of oxygen desaturation is relatively mild [31–33].

Diagnosis

Then diagnosis of nocturnal asthma requires the appropriate combination of clinical

symptoms such as nocturnal wheezing, cough, and shortness of breath associated with
a greater than 10% fall in overnight peak flow rates. The treatment of nocturnal asthma
is similar to the treatments offered to diurnal asthma control: inhaled bronchodilators,
inhaled corticosteroids or oral corticosteroids, and leukotriene inhibitors. Some
patients may require treatment with longer-acting beta agonist or a theophyline prepa-
ration in order to experience good control of nocturnal symptoms [34, 35].

Sleep and Restrictive Lung Disorders

Restrictive lung disorders are those in which disorders of lung parenchyma, respira-
tory muscles, or the surrounding chest results in smaller than normal lung volumes.
There is relatively little data regarding sleep in restrictive lung disorders caused by
210 C.W. Atwood, Jr.

parenchymal lung disease such as pulmonary fibrosis. In contrast, the neuromuscular

and chest wall disorders have received more attention because of the recognition
that noninvasive NIPPV results in significant physiological and clinical improve-
ments for the patient suffering from these disorders.

Chest Wall Disorders

Chest wall disorders in which the chest is abnormally noncompliant can lead to
respiratory failure. Severe obesity (BMI > 50 kg/m2) and kyphoscoliosis are the two
most common chest wall disorders. Post polio syndrome can lead to chest wall
dysfunction but this is becoming less common with the Unites States’ eradication of
polio. Post polio syndrome can affect the chest wall with or without spinal curvature
(scoliosis). Another vanishing cause of chest wall stiffening is “collapse” therapy for
tuberculosis. This procedure led to both a stiffened chest wall that was made to
collapse by resecting anterior ribs and allowing the anterior chest wall, no longer
supported by ribs, to collapse on the lung. This caused a large degree of atelectatic
lung and a restrictive pulmonary condition. This condition has now disappeared since
we have been in the antibiotic era of tuberculosis therapy for the past 50 years.
Kyphoscoliosis refers to a combination of lateral as well as anterior–posterior
curvature of the spine. Some patients may have pure scoliosis or appear kyphosis
but most have a combination of the two. Chest wall deformity such as this is far
more common in females than males. The prevalence of severe kyphoscoliosis is
decreasing, owing to early intervention and corrective surgery before the development
of respiratory complications. The current prevalence of kyphoscoliosis about
1:10,000 [36, 37].

Pathophysiology of Hypoxemia

Respiratory mechanics in kyphoscoliosis demonstrate a significant restrictive defect

[37], due to a stiffened chest and abnormally positioned respiratory muscles. Patients
with kyphoscoliosis have smaller functional residual capacity and smaller oxygen
stores in the lungs; thus, severe nocturnal hypoxemia is common. Patients with
kyphoscoliosis may have rapid and severe desaturation during sleep and may tend
to adopt a more rapid and shallow breathing pattern, which is probably advantageous
from a muscle energy conservation standpoint but comes at the expense of ventila-
tion; carbon dioxide rises [36]. Hypoxemia develops due to increasing ventilation–
perfusion mismatch from increasing atelectasis from the changes in chest wall and
diaphragm position. Increasing dyspnea and worsening hypoventilation lead to
sleep fragmentation and poor sleep quality. In addition, patients with kyphoscoliosis
are highly susceptible to respiratory failure if the respiratory drive is affected.
This can be due to the inappropriate use of medications, for example, opiates
11 Sleep and Lung Disease 211

or sedative/hypnotics. Advanced kyphoscoliosis patients should be given oxygen

judiciously since respiratory drive may be decreased by administration of supple-
mental oxygen above physiological levels [38].

Diagnosis

The diagnosis of kyphoscoliosis is based on clinical and radiological assessment.

Patients are at risk of ventilatory problems when the main curvature of the spine
reaches an angle of at least 100°. Arterial blood gases should be measured to assess
ventilation and oxygenation. If a PaCO2 of 45 mmHg or higher is found then
consideration should be given to nocturnal ventilation support [39]. In such patients
sleep disruption, sleep fragmentation and, desaturations and elevated PaCO2 con-
tribute to sleep-related complaints, which are common as the condition advances.

Therapy

The treatment goal is to improve ventilation, starting with NIPPV; however, some
patients may require mechanical ventilation through a tracheostomy [39]. Kyphoscoliosis
responds well to NIPPV, with improvement in sleep quality and quality. Although there
are not randomized clinical trials comparing NIPPV with another therapy, the accu-
mulated clinical experience has shown the value of this therapy.

Interstitial Lung Disease

The Interstitial Lung Diseases are another group of disorders with restrictive physi-
ology. This is a heterogeneous group of disorders, which affect lung parenchyma,
resulting in scarring and stiffening of the lung and increases in its elastic recoil. The
interstitial lung diseases do not result in significant hypoventilation until they reach
end-stage. This is because the parental scarring and inflammation tends to stimulate
hyperpnea, which has the effect of lowering PaCO2 [40]. Sleep disruption, hypox-
emia, and dyspnea may affect the quality in these patients. Cough may also be a
debilitating symptom at night.

Diagnosis

Sleep studies may be considered if there is a clinical suspicion of sleep apnea or other
sleep disorders. It is particularly important to at least measure overnight oxygenation in
patients demonstrating erythrocytosis since this may be a clinical clue to more severe
levels of hypoxemia. Polysomnography has shown that interstitial lung disease patients
have fragmented sleep, many arousals, more stage I sleep, and less REM sleep [41].
212 C.W. Atwood, Jr.

Treatment

Interstitial lung disease patients may benefit from nocturnal oxygen therapy to treat
underlying hypoxemia. However, noninvasive ventilation may be difficult, in light
increased respiratory drive. Most of what we understand to be true about the effect
of oxygen therapy on hypoxemia comes from studies of patients with severe obstructive
airways disease [42]. Unfortunately, the literature on oxygen therapy in hypoxemic
patients with interstitial lung disease is limited. Appropriate positive airway pressure
or other treatments should be considered in patients who have concomitant OSA.
Otherwise, oxygen therapy alone for patients with nocturnal hypoxemia alone will
be sufficient.

Sleep and Obesity: Hypoventilation Disorders

Obesity hypoventilation syndrome (OHS) consists of daytime and nocturnal

hypoventilation after excluding other causes of alveolar hypoventilation, such as
COPD, restrictive disorders, or neuromuscular diseases. The prevalence of OHS is
unknown. As its name suggests, this condition afflicts obese individuals. Yet, only
a minority of obese patients will have obesity hypoventilation (10–20%) [39]. This
degree of obesity may be more common in women than in men but more men
appeared to be diagnosed with OHS.
The major risk factor is obesity. There may be other factors relating to control of
breathing which predispose one to developing obesity hypoventilation, but these
mechanisms remained poorly understood and are not easily clinically identifiable.

Pathogenesis

Abnormalities in respiratory mechanics, control of breathing and state changes

related to sleep vs. wakefulness seem to be the most important factors in development
of OHS [38, 39, 43]. Abnormalities in lung mechanics are more pronounced in
patients with OHS compared to patients with eucapnic morbid obesity [43]. Reduced
ventilatory drive may also contribute to the development of OHS. Patients with
OHS have a blunted ventilatory drive compared to obese individuals without OHS.
Whether the defect in ventilator drive is acquired or familial is unclear [44–46].
Several biochemical factors may influence the development of OHS, including
leptin and serum bicarbonate levels. Leptin is an adipose tissue-derived hormone
with many different effects, including serving as a respiratory stimulant. In one
animal model, the leptin-deficient ob/ob mouse, exogenous administered to the
mice caused a reversal in OHS [47]. Obesity hypoventilation and OSA are leptin-
resistant states. This fits the empiric evidence that leptin levels are high, not low, in
OHS and OSA. The concept of central leptin resistance has been proposed to explain
11 Sleep and Lung Disease 213

high leptin levels in OHS patients who also seem to have blunted respiratory
responses [48, 49]. Metabolic compensation for chronic respiratory acidosis is asso-
ciated with accumulation of bicarbonate and blunted chemoresponsiveness. This
tends to promote daytime hypercapnia [38].

Clinical Features

In addition to symptoms associated with morbid obesity, OHS patients may present
with peripheral edema, venous stasis, pulmonary hypertension, and cor pulmonale.
Dyspnea on exertion is common [38, 39]. OHS patients consume a higher amount
of health services compared to very obese but eucapnic patients [50]. Obesity
hypoventilation patients exhibit greater degree of cardio metabolic complications
than patients who have OSA or severe eucapnic obesity alone.

Diagnosis

The diagnosis of OHS consists of an elevated PaCO2 in an awake patient. The symp-
toms of OHS are not adequately specific to be use in making a diagnosis. The diag-
nosis often requires a high index of suspicion. Elevated serum bicarbonate is a
useful laboratory clue to the possibility of CO2 retention. A serum bicarbonate level
³27 mEq/L is highly sensitive (92%) but not specific (50%) for the presence of an
elevated CO2 level. Pulse oximetry is not helpful in diagnosing OHS. Transcutaneous
CO2 measurements may be very helpful in documenting elevation in CO2 and
strongly suggesting the disorder is present [39].

Therapy

The treatment of choice for OHS is positive pressure therapy, either CPAP or bilevel
positive airway pressure (BPAP). Both modalities will improve alveolar ventilation.
However, BPAP is capable of providing greater ventilator support than CPAP. If the
difference between the inspiratory positive airway pressure (IPAP) and the expiratory
positive airway pressure (EPAP) is at least 6, then ventilation is likely to be effective.
Longer-term studies have suggested that positive airway pressure therapy remains
effective for OHS patients and result in improved arterial blood gas values, daytime
sleepiness, and ventilatory responsiveness to carbon dioxide re-breathing [51]. Studies
have also demonstrated decreased health care utilization of decreased hospitalizations
than the patients with OHS treated with positive airway pressure therapy [50]. In addi-
tion to positive airway pressure therapy, some patients may benefit from low flow
oxygen either alone or with BPAP to maintain adequate oxygen saturation.
214 C.W. Atwood, Jr.

Surgery may be a useful adjunct to positive airway pressure therapy for obesity
hypoventilation. Upper airway surgery, which is sometimes effective for OSA, does
not have a significant role in OHS. Tracheostomy, however, may be effective treatment.
Nocturnal ventilation through a tracheostomy is an effective method of increasing
alveolar ventilation. Monitoring arterial blood gases periodically is essential for
monitoring the effectiveness of the therapy [39].

Weight Loss

Weight loss is an effective treatment for OHS. However, it is difficult to achieve and
maintain long-term. Bariatric surgery, with the goal of achieving and sustaining
significant weight loss, is an option for obese patients with significant hypoventila-
tion. Bariatric surgery is increasingly accepted as a definitive treatment for severe
obesity. The degree of weight loss that is possible with bariatric surgery has been
shown to improve gas exchange and lung volumes, especially the expiratory reserve
volume [52]. Unfortunately, we have few long-term data in patients with well-
described OHS who have undergone bariatric surgery and then continued in follow-up
to establish response of OHS to significant weight loss. However, if we extrapolate
from the experience with OSA, then we can expect significant improvement in
pulmonary physiological parameters and OHS symptoms, although there will be
many patients who are not fully cured of the OHS [53].

Summary of Keypoints

• Sleep disturbances are common in chronic respiratory conditions. These include

poor sleep quality and worsening gas exchange.
• REM sleep is characterized by significant alveolar hypoventilation, due to skeletal
muscle atonia, reduced during volume, and subsequent worsening of ventilation/
perfusion mismatching.
• Nocturnal hypoxemia is due to a combination of hypoventilation ventilation/
perfusion mismatching.
• Nocturnal oximetry is sufficient for the diagnosis of nocturnal hypoxemia.
Polysomnography should be reserved for situations where a specific sleep disor-
der, such as OSA is suspected.
• Noninvasive ventilation may be beneficial in patients with COPD and chronic
ventilatory failure, chest wall disease, or obesity hypoventilation.
• Clinicians should specifically inquire about sleep in patients with chronic lung
disease, including poor nocturnal sleep, insomnia, morning headache, and daytime
hypersomnia.
11 Sleep and Lung Disease 215

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11 Sleep and Lung Disease 217

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Chapter 12
Central Sleep Apnea

M. Safwan Badr

Keywords Central apnea • Hypoventilation • Hyperventilation • Hypocapnia

• Cheyne–Stokes respiration • CPAP • Adaptive servo-ventilation

Central sleep apnea is a manifestation of breathing instability in a variety of clinical

conditions and is often bundled under the rubric of obstructive sleep apnea. Central
sleep apnea occurs because of a transient cessation of ventilatory motor output,
under several physiologic or pathologic conditions. This chapter will address the
pathogenesis, clinical features, and management of central sleep apnea.

Determinants of Central Apnea During NREM Sleep

Hypocapnia

The sleep state (specifically non-rapid eye movement or NREM sleep) removes the
wakefulness “drive to breathe” and renders respiration critically dependent on
chemical influences, especially PCO2. Central apnea results if arterial PCO2 is
lowered below a highly sensitive “apneic threshold” [1, 2]. Hypocapnia is a potent
but not an omnipotent mechanism of reduced ventilatory motor output during
NREM sleep. Several factors modulate and mitigate the effects of hypocapnia on
ventilatory motor output and promote stability of respiration

M.S. Badr (*)

Department of Internal Medicine, Harper University Hospital, Wayne State University
School of Medicine, 3990 John R Street, Detroit, MI 48201, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 219
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_12,
© Springer Science+Business Media, LLC 2012
220 M.S. Badr

Short-Term Potentiation

Actively induced hyperventilation (such as hypoxic hyperventilation) is associated

with activation of an excitatory neural mechanism referred to as short-term poten-
tiation (STP) [3–5], which results in a gradually return of ventilation toward the
baseline upon cessation of the stimulus to breathe. STP has been demonstrated in
humans as well as in animals and is unaffected by the state of consciousness. STP
may play a significant role in preserving rhythmic respiration by preventing
abrupt drop in ventilation during transient hypocapnia such as following brief
hypoxia or transient arousal. In fact, central apnea rarely occurs following termina-
tion of brief hypoxia, despite hypocapnia at or below the apneic threshold [3, 5].
Similarly, although hypocapnia occurs during transient arousals from sleep, the
activation of STP may mitigate the occurrence of central apnea under these condi-
tions [6]. However, prolonged hypoxia may abolish STP by, which may explain the
development of periodic breathing after 20–25 min of hypoxia and the occurrence
of central apnea upon termination of prolonged hypoxic exposure [5, 7].

Duration of Hyperpnea

The duration of hyperpnea is another important determinant of reduced ventilatory

motor output following hyperventilation. Central apnea does not usually occur
following brief in sleeping humans [8] or dogs [9] possibly due to insufficient reduction
in PCO2 at the level of the central chemoreceptors.
In summary, the balance between hypocapnia and short-term potentiation
determines the occurrence of post-hyperventilation apnea during stable sleep, while
the duration of hyperventilation may determine whether the reduction in medullary
PCO2 is sufficient for the development of central apnea.

Role of Upper Airway Reflexes

While hypocapnia is the most common influence leading to central apnea, other
mechanisms may also induce central apnea. For example, negative pressure-induced
deformation of the isolated upper airway causes central apnea in dogs during both
wakefulness and sleep [10]. Whether such reflexes contribute to the developments
of central apnea in sleeping humans remains speculative. Conversely, central apnea
occurs more frequently in the supine position [11–13] and may be reversed with
nasal continuous positive airway pressure (CPAP) [14]. Likewise, there is evidence
of supine dependency including that the lateral position amelioration of severity of
central apnea and Cheyne–Stokes respiration [11–13].
12 Central Sleep Apnea 221

Mechanisms Perpetuating Breathing Instability

Central apnea does not occur as a single event, but as cycles of apnea/hypopnea
alternating with hyperpnea. Ventilatory control during sleep operates as a negative-
feedback closed-loop cycle to maintain homeostasis of blood gas tensions within a
physiologic range. Many authors have adopted the engineering concept of “loop
gain” as a measure of ventilatory stability or susceptibility to central apnea and recur-
rent periodic breathing [15]. Loop gain represents the overall response of the plant
(representing the lung and respiratory muscles), the controller (representing the
ventilatory control centers and the chemoreceptors) and the delay, dilution and diffu-
sion inherent in transferring the signal between the plant and the controller. A detailed
discussion of the dynamics of ventilatory control is beyond the scope of this chapter
there are several excellent reviews that have discussed this aspect in detail [16–18].
The occurrence of central apnea is associated with several consequences that
conspire to promote further breathing instability:
• Once ventilatory motor output ceases, rhythmic breathing does not resume at
eupneic arterial PCO2 (PaCO2) due to inertia of the ventilatory control system; an
increase in PaCO2 by 4–6 mmHg above eupnea is required for resumption of
respiratory effort [19].
• Central apnea is associated with narrowing or occlusion of the pharyngeal air-
way [20]. Thus, resumption of ventilation requires opening of a narrowed or
occluded airway and overcoming tissue adhesion forces [21] and cranio-facial
gravitational forces.
Termination of central apnea is associated with variable changes in arterial blood
gases (hypoxia and hypercapnia) and transient EEG arousal, resulting in ventilatory
overshoot, subsequent hypocapnia, and a recurrence of apnea/hypopnea. This sequence
explains why apnea rarely occurs as a single event (i.e., “apnea begets apnea”) and why
there is an overlap between central and obstructive apnea (upper airway obstruction
often follows central apneas upon resumption of respiratory effort, i.e., mixed apnea).

Pathophysiologic Classification of Central Sleep Apnea

Central apnea syndrome may be present in a diverse group of conditions includ-

ing heart failure and obstructive sleep apnea. The ICSD lists several categories
of central apnea: (1) Primary Central Sleep Apnea, (2) Central Sleep Apnea
Due to Cheyne–Stokes Breathing Pattern, (3) Central Sleep Apnea Due to
Medical Condition Not Cheyne–Stokes, (4) Central Sleep Apnea due to High
Altitude Periodic Breathing, (5) Central Sleep Apnea Due to Drug or Substance
use. Central apneas are caused either by hyperventilation or hypoventilation.
222 M.S. Badr

Primary CSA, CSA-CSR, and CSA at high altitude are examples of CSA-related
to hyperventilation. Central Sleep Apnea Due to Drug or Substance use is due to
hypoventilation, whereas central apnea associated with other medical conditions
may be due to either hyperventilation or hypoventilation. The underlying mecha-
nisms influence the choice of therapy including optimization of medical therapy
in central apnea associated with other conditions such as heart failure, hypothy-
roidism, or acromegaly.
The level of arterial PCO2 during wakefulness is often used to classify central
apnea as hypercapnic or non-hypercapnic. However, such classification does not
capture the underlying pathogenesis as apnea represents hypoventilation or a conse-
quence of hyperventilation.

Central Sleep Apnea Secondary to Hypoventilation

The sleep state is associated with reduced ventilatory motor output, increased upper
airway resistance and hypoventilation. This physiologic constellation carries pathologic
consequences in patients with an underlying abnormality in ventilatory control or
impaired pulmonary mechanics. Most afflicted patients suffer from a central nervous
system disease (e.g., encephalitis), neuromuscular disease (e.g., post-polio syndrome),
or severe abnormalities in pulmonary mechanics (e.g., kyphoscoliosis [22]). Thus,
the hallmark of this disease is alveolar hypoventilation representing nocturnal
ventilatory failure or worsening of the underlying chronic disease. Arousal from
sleep restores alveolar ventilation to a variable degree; resumption of sleep reduces
ventilation in a cyclical fashion.
Central apnea secondary to hypoventilation does not necessarily meet the strict
definition of “apnea,” since feeble ventilatory motor output may persist albeit below
the thresholds required to preserve alveolar ventilation. Likewise, it may not meet the
definition of “central” in patients with respiratory muscle disease or skeletal
deformities. Consequently, the presenting clinical picture includes both features of
the underlying ventilatory insufficiency (e.g., morning headache, cor pulmonale,
peripheral edema, polycythemia, and abnormal pulmonary function tests) and
features of the sleep apnea/hypopnea syndrome (e.g., poor nocturnal sleep, snoring,
and daytime sleepiness).
A rare but interesting group of patients present with primary alveolar hypoventi-
lation manifesting by daytime hypoventilation without an apparent identifiable
cause and blunted chemo responsiveness [23, 24]. Congenital central hypoventilation
syndrome (CCHS) results from a mutation in the gene that encodes the homeobox
(PHOX) 2B gene.
The mechanism(s) responsible for hypercapnic central sleep apnea in a given
patient influence(s) the management strategy, which aims to restore effective alveolar
ventilation during sleep. Treatment of choice is assisted ventilation; Nasal CPAP
and supplemental oxygen are unlikely to alleviate the condition.
12 Central Sleep Apnea 223

Central Apnea Secondary to Hyperventilation

Hypocapnia secondary to hyperventilation is the most common underlying

mechanism of central apnea. A typical patient with non-hypercapnic central apnea
has no evidence of a neuromuscular disorder, abnormal lung mechanics, or impaired
responses to chemical stimuli. Accordingly, apnea is a result of a transient instability
rather than a ventilatory control defect.
How does the first apnea begin? Several transient perturbations may trigger the
initial event, including oscillation in sleep state [25], or transient hypoxia possibly
due to retention of secretions or reduced lung volumes at sleep onset. Thus, hypoxia
stimulates ventilation, subsequently leading to hypocapnia and apnea. The occurrence
of apnea initiates the repetitive process of apnea-hyperpnea and leads to sustained
breathing instability, manifested as periodic breathing (see above). In summary,
non-hypercapnic central apnea is a heterogeneous entity that may be an idiopathic
or a secondary condition. The pathogenesis may vary depending upon the clinical con-
dition. However, hypocapnia secondary to hyperventilation is the common denomi-
nator in this group of disorders.

Central Apnea Risk Factors

Sleep State

Transient breathing instability and central apnea often occur during the transition
from wakefulness to NREM sleep. As sleep state oscillates between wakefulness
and light sleep [26–28] the level of PaCO2 is at or below the hypocapnic level
required to maintain rhythmic breathing during sleep (i.e., the “apneic threshold”),
resulting in central apnea; recovery from apnea is associated with transient
wakefulness and hyperventilation. The subsequent hypocapnia elicits apnea upon
resumption of sleep. Consolidation of sleep alleviates the oscillation in sleep and
respiration and stabilizes PaCO2 at a higher set point above the apneic threshold.
Interestingly, central apnea may occur without preceding hyperventilation at the
transition from alpha to theta in normal subjects is associated with prolongation of
breath duration [29]. Although most authors believe that central apnea at sleep onset may
be a normal phenomenon; the natural history of this “phenomenon” is unknown.
Central sleep apnea is uncommon during REM sleep as many studies suggest
that breathing during REM sleep is impervious to chemical influences (REF), pos-
sibly due to increased ventilatory motor output during REM sleep [30, 31] relative
to NREM sleep. In addition, there is evidence in animal studies that hypocapnia,
per se, may decrease the amount of REM sleep [32]. The major barrier to answering
this question in humans is the difficulty in conducting such experiments without
disrupting REM sleep.
224 M.S. Badr

The loss of intercostal and accessory muscle activity during REM sleep leads to
a reduction of alveolar ventilation. This may manifest as apparent central apnea or
hypopnea in patients with compromised lung mechanics or neuromuscular disease.
If severe diaphragm dysfunction is present, nadir tidal volume may be negligible
and the event may appear as central apnea. Thus, central apnea during REM sleep
represents transient hypoventilation rather than post-hyperventilation hypocapnia.

Age and Gender

Central sleep apnea is more prevalent in older adults relative to middle-aged individuals
[33–35] physiologically; sleep state oscillations may precipitate central apnea in
older adults [36]. Increased prevalence of co-morbid conditions such as thyroid
disease [37], congestive heart failure [38], atrial fibrillation [39], and cerebrovascular
disease [40], may also contribute to increased susceptibility to develop central apnea
in older adults.
Central sleep apnea is uncommon in pre-menopausal women [41]. There is evidence
that women are less susceptible to the development of hypocapnic central apnea
during relative to men following mechanical ventilation. Physiologically, the
hypocapnic apneic threshold is higher in men relative to women. Using nasal
mechanical ventilation during stable NREM sleep, Zhou et al. [2] have shown that
the apneic threshold was −3.5 vs. −4.7 mmHg below room air level in men and
women respectively. This difference was not due to progesterone. In fact, administra-
tion of testosterone to healthy pre-menopausal women for 12 days resulted in an
elevation of the apneic threshold and a diminution in the magnitude of hypocapnic
required for induction of central apnea during NREM sleep [42]. Conversely, sup-
pression of testosterone with leuprolide acetate in healthy males decreases the
hypocapnic apneic threshold and potentially stabilizing respiration [43]. Thus, male
sex hormones are the most likely factor elevating the apneic threshold in men.

Medical Conditions

Sleep apnea is highly prevalent in patients with CHF [38, 44–46]. Javaheri et al.
[45] demonstrated that 51% of male patients with CHF had sleep-disordered
breathing; 40% had central sleep apnea, and 11% obstructive apnea. Risk factors for
CSA in this group of patients include male gender, atrial fibrillation, age >60 year,
and daytime hypocapnia (PCO2 < 38 mmHg during) [47]. Risk factors for OSA
differed by gender; the only independent determinant in men was Body mass index
(BMI), whereas age over 60 was the only independent determinant in women.
Hyperventilation is a common breathing pattern in patients with CHF, who dem-
onstrate daytime hypocapnia and minimal or no rise in PET CO2 from wakefulness to
sleep [48]. Chronic hyperventilation results in decreased plant gain [49, 50], which
12 Central Sleep Apnea 225

mitigates the magnitude of hypocapnia for a given increase in alveolar ventilation.

In other words, steady-state hyperventilation and hypocapnia are potentially
stabilizing rather than destabilizing as is commonly thought. Increased propensity
to central apnea in patients with CHF is due to increased hypocapnic chemosensi-
tivity (increased controller gain).
Sleep apnea is also common after a cerebrovascular accident (CVA) [40]; with
central apnea being the predominant type in 40% of patients of sleep apnea after a
CVA [51, 52]. Likewise, central apnea occurs in 30% of patients who are on stable
methadone maintenance treatment [53]. Finally, several medical conditions predis-
pose to the development of central apnea including hypothyroidism, acromegaly, and
renal failure have an unexpectedly high prevalence of sleep apnea [54–56]. Nocturnal
hemodialysis is associated with improvement in sleep apnea indices [56].
Some patients with central apnea have no apparent risk factor and are deemed to
have “idiopathic central apnea”; typically, these patients demonstrate increased chemo
responsiveness and sleep state instability [57]. It is plausible that these patients will
have occult cardiac or metabolic disease. For example, idiopathic central sleep
apnea is more prevalent in patients with atrial fibrillation [39].

Clinical Features and Diagnosis

The clinical presentation includes features of the underlying disease and features of
sleep apnea syndrome. Patients with central apnea secondary to hyperventilation
may present with the usual symptoms of sleep apnea syndrome. Alternatively, they
may present with insomnia and poor nocturnal addition. Frequent oscillation
between wakefulness and stage 1 NREM sleep may promote sleep fragmentation
and poor nocturnal sleep as the presenting symptoms.
Central sleep apnea may also be a found as an incidental polysomnographic
finding in a patient with obstructive sleep apnea, either on the initial diagnostic
study or after restoring upper airway patency with nasal CPAP. The latter is
referred to as “complex sleep apnea,” implying a distinct clinical entity. However,
it is likely that this phenomenon represents unmasking of the underlying breath-
ing instability in patients with obstructive sleep apnea and may resolve spontane-
ously [58, 59].
Nocturnal polysomnography is the standard diagnostic method including
measurement of sleep and respiration, including detection of flow, measurement of
oxyhemoglobin saturation, and detection of respiratory effort. Detection of respira-
tory effort is important to distinguish central from obstructive apnea. Most clinical
sleep laboratories utilize surface recording of effort to detect displacement of the
abdominal and thoracic compartments instead of esophageal pressure recording.
The presence of cardiogenic oscillations (pulse artifacts) on the flow signal has been
used as an indirect index of central etiology. The underlying rationale is the pulse
artifacts represent transmission of a pulse waveform from the thorax, and hence
indicates a patent upper airway that allows the transmission of cardiogenic oscillation.
226 M.S. Badr

Morrell et al. [60] used fiber optic naso-pharyngoscopy to evaluate upper airway
patency during central apnea; cardiogenic oscillations were present even when the
airway is completely occluded. Thus, the presence of cardiogenic oscillations does
not prove upper airway patency or central etiology.

Management

Central apnea syndrome is a disorder with protean manifestations and underlying

conditions. The presence of co-morbid conditions and concomitant obstructive sleep
apnea influence therapeutic approach significantly. Specific therapeutic options
include positive pressure therapy, pharmacologic therapy, and supplemental oxygen.

Positive Pressure Therapy

Central apnea may respond to nasal CPAP therapy, especially if in combination

with episodes of obstructive or mixed apnea. If a concomitant clinical condition is
present, such as congestive heart failure, hypothyroidism, or acromegaly, optimiza-
tion of medical therapy is also required and may ameliorate the severity of central
apnea. Likewise, central sleep apnea in patients with obstructive sleep apnea may
resolve with alleviation of upper airway obstruction with positive pressure therapy.
Many patients with idiopathic central sleep apnea receive a trial of nasal CPAP,
which has been shown to reverse central sleep apnea, even in the absence of
obstructive respiratory events [14], especially supine-dependent central sleep apnea.
The response may be due to preventing upper airway occlusion during central apnea
and subsequent ventilatory overshoot [20]. Prevention of ventilatory overshoot may
explain the reported combination of reduced apnea frequency and increased PCO2
after CPAP [61]. Nasal CPAP is the initial option during a therapeutic titration
study, despite the lack of systematic studies on nasal CPAP therapy in patients with
idiopathic central apnea.
The exuberance regarding nasal CPAP therapy in patients with central apnea and
CHF did not withstand the rigors of controlled clinical trials. The Canadian
Continuous Positive Airway Pressure trial, or Can PAP [62] tested the hypothesis
that CPAP would improve the survival rate without heart transplantation in patients
with heart failure and central sleep apnea. The study enrolled 258 patients who
had heart failure and central sleep apnea; participants were randomly assigned to
the nasal CPAP treatment group (n = 128) or no CPAP (130 patients). Duration of
follow-up was for a mean of 2 years. There was greater improvement in the CPAP
group at 3 months relative to the placebo group as evidenced by greater reductions
in apnea-hypopnea index, ejection fraction, mean nocturnal oxyhemoglobin sat-
uration, plasma nor-epinephrine levels, and the distance walked in 6 min at 3
months. Nevertheless, there was no difference in the overall event rates (death and
heart transplantation) between the two groups. Thus, nasal CPAP had no effect on
12 Central Sleep Apnea 227

survival, despite the effect on the “severity” of central apnea and several intermediate
outcome variables. Therefore, current evidence does not support the use of CPAP to
extend life in patients who have heart failure and central sleep apnea.
Non-invasive positive pressure ventilation (NIPPV) using pressure support mode
(bi-level nasal positive pressure) is effective in restoring alveolar ventilation during
sleep. Clinical indications include nocturnal ventilatory failure and central apnea
secondary to hypoventilation. There is evidence that NIPPV exerts a salutary effect
on survival in patients with ventilatory failure secondary to amyotrophic lateral scle-
rosis [63]. It is unclear whether NIPPV exerts a similar effect in other neuromuscular
conditions associated with nocturnal ventilatory failure. However, the overall evidence
supports the use of NIPPV in a pressure support mode to treat central sleep apnea
secondary to hypoventilation, such as neuromuscular or chest wall-related nocturnal
hypoventilation. If the ventilatory motor output is insufficient to “trigger” the
mechanical inspiration, adding a backup rate ensure adequate ventilation.
Treatment of central apnea secondary to hyperventilation using nasal pressure
support ventilation in the bi-level mode may result in worsening of central apnea
and breathing instability owing to augmented ventilatory overshoot and hypocapnia
[64]. The work of Meza et al. [65] provides empiric evidence that pressure-support
ventilation results in periodic breathing and recurrent central apnea when the pressure
gradient is above 7 cm H2O. The addition of a backup rate would be required to
maintain stable respiration, which would convert ventilatory support to controlled
mechanical ventilation. In general, Bi-level positive pressure therapy is unlikely to
alleviate central apnea, without a back up rate. Nevertheless, Bi-level PAP may
ameliorate central apnea that accompanies severe obstructive apnea by preventing
upper airway obstruction and ventilatory overshoot.
Recent technological advances allowed for variations in the mode of delivering
positive pressure ventilation. One example is Adaptive Servo-Ventilation (ASV),
which provides a small but varying amount of ventilatory support and a back up
rate, against a background of low level of CPAP. The device maintains ventilation
at 90% of a running 3-min reference period; thus, changes in respiratory effort
results in reciprocal changes in the magnitude of ventilatory support. There is evidence
that ASV is more effective than CPAP, Bi-level pressure support ventilation, or
increased dead space in alleviating central sleep apnea [66]. However, there are
no long-term studies examining the long-term effectiveness or outcome. Therefore,
the decision to initiate ASV hinges on the efficacy of the treatment in normalizing
AHI, patient preference, payers preference, and the availability of the requisite
support for adherence or troubleshooting.

Pharmacological Therapy

Pharmacologic therapy for central apnea remains elusive, and there are no controlled
clinical trials demarcating the boundaries of effectiveness [67]. Several small clinical
trials indicate that acetazolamide or and theophylline may be beneficial in the
treatment of central apnea [68, 69]. Acetazolamide is a weak diuretic and a carbonic
228 M.S. Badr

anhydrase inhibitor that causes mild metabolic acidosis. Acetazolamide ameliorates

central sleep apnea when administered as a single dose of 250 mg before bedtime
[68]. Likewise, theophylline ameliorates the severity of Cheyne–Stokes respiration
in patients with CHF [69], without adverse effect on sleep architecture. Pharmacologic
therapy remains an unfulfilled opportunity awaiting further research.

Supplemental O2 and CO2

Several studies have demonstrated a salutary effect of supplemental O2 in patients

with idiopathic central sleep apnea and patients with CHF-CSR [70]. Several potential
mechanisms may explain the stabilizing effect of supplemental oxygen on respira-
tion. Oxygen dampens peripheral chemoreceptor responsiveness and minimizes
the subsequent ventilatory overshoot. In addition, prolonged hyperoxia stimulates
respiration, perhaps by elevating cerebral PCO2 by the Haldane effect. Acute
administration of oxygen is associated with diminished propensity to develop
central apnea in normal subjects during sleep [71]. While long-term clinical trials are
lacking, supplemental oxygen therapy is a promising adjunct for central apnea,
especially in patients with CHF. Likewise, supplemental CO2 abolishes central
apnea in patients with pure central sleep apnea, by raising PCO2 above the apneic
threshold [72, 73]. However, this therapy is not practical given the need for a closed
circuit to deliver supplemental CO2.

Approach in Selected Clinical Syndromes

The heterogeneity of central sleep apnea dictates individualized treatment approach,

including optimal treatment of underlying medical conditions and attention to
potential medication effects. A trial of nasal CPAP in the sleep laboratory is warranted
to ascertain the magnitude of improvement with CPAP alone. The use of BPAP in a
pressure support mode is likely to aggravate the severity of central apnea, unless
accompanied by a backup rate. ASV may be beneficial in patients with CSR
secondary to CHF who do not respond to nasal CPAP alone. Supplemental O2 may
be beneficial in patients with central apnea that persists on nasal CPAP, especially
in patients with CHF-CSR.

Summary

The pathogenesis of central sleep apnea varies depending on the clinical condition.
Sleep-related withdrawal of the ventilatory drive to breathe is the common denomi-
nator among all cases of central apnea, whereas hypocapnia is the final common
12 Central Sleep Apnea 229

pathway leading to apnea in non-hypercapnic central apnea. The pathophysiologic

heterogeneity may explain the protean clinical manifestations and the lack of a single
effective therapy for all patients.

Summary of Keypoints

• Central sleep apnea is not a single clinical entity; instead, it is a manifestation of

breathing instability in a variety of clinical conditions. Central apnea syndrome
occurs may be present in a diverse group of conditions including heart failure
and obstructive sleep apnea.
• Central apneas is caused wither by hyperventilation or hypoventilation.
Hypocapnia is the most potent and ubiquitous trigger of central sleep apnea.
Central apnea rarely occurs as a single event; instead, it manifests by cycles of
apnea/hypopnea alternating with hyperpnea.
• Central apnea is classified into the following specific categories according to the
ICSD-2: (1) Primary Central Sleep Apnea, (2) Central Sleep Apnea Due to Cheyne–
Stokes Breathing Pattern, (3) Central Sleep Apnea Due to Medical Condition
Not Cheyne–Stokes, (4) Central Sleep Apnea due to High Altitude Periodic
Breathing, (5) Central Sleep Apnea Due to Drug or Substance use. The underlying
mechanisms influence the choice of therapy including optimization of medical
therapy in central apnea associated with other conditions such as heart failure,
hypothyroidism, or acromegaly.
• Advanced age, male gender, post-menopausal state in women and sleep–wake
transition are physiologic determinants of central apnea. In contrast, central
apnea is less common in REM sleep. Medical conditions which are associated
with higher risk of central sleep apnea include CHF, CVA, Chronic narcotics
users, acromegaly, chronic renal failure, and hypothyroidism.
• Clinical features are a combination of sleep apnea features and co-morbid
conditions. The diagnosis requires nocturnal polysomnography. Specific therapeutic
options include positive pressure therapy, pharmacologic therapy, and supple-
mental oxygen. Nasal CPAP is the recommended initial treatment of choice.

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Chapter 13
Insomnia: Etiology, Clinical Manifestations,
and Morbidity

Clare E. Gargaro, Thomas Roth, and Christopher L. Drake

Keywords Insomnia • Predisposition • Stress • CBT-I • Pathophysiology

• Treatment • Comorbidity

Introduction

Insomnia is a serious public health concern with high rates of patients presenting to
both general and specialty care clinics with sleep disturbance as a complaint. In
clinical settings, the prevalence of insomnia-related symptoms is much higher than
in the general population and is attributable to increased medical and psychiatric
disorders [1]. Patients with chronic obstructive pulmonary disease (COPD) have a
particularly high prevalence of insomnia [2], and insomnia has considerable implica-
tions for pulmonary function in those with COPD and other respiratory disorders [3].
Insomnia is also an under recognized and under treated problem. Partly due to a lack
of training in the recognition and management of sleep disorders [4]. Insomnia has a
significant negative impact on diverse functional outcomes including fatigue,
increased risk for accidents, impairments in memory and attentional processing,
and increased risk for depression and substance use. This chapter details the diag-
nostic criteria for insomnia, characteristics of its symptomology, medical and
psychiatric co-morbidity, pathophysiology, as well as individual and societal conse-
quences. While the non-specific nature of insomnia symptoms have contributed to

C.E. Gargaro
Department of Sleep Medicine, Henry Ford Hospital, Detroit, MI, USA
T. Roth • C.L. Drake (*)
Sleep Disorders and Research Center, Henry Ford Hospital, 2799 W Grand Boulevard,
Detroit, MI 48334, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 233
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_13,
© Springer Science+Business Media, LLC 2012
234 C.E. Gargaro et al.

the variability in diagnosing and treating an insomnia disorder, it is important for

the pulmonologist to recognize and treat this common medical condition.
The National Institutes of Health State-of-the-Science conference brought to
attention the fact that insomnia is most often co-morbid with other medical and
psychiatric conditions [5]. However, while previously defined as a symptom
secondary to another disorder, insomnia is now considered a disorder requiring
direct treatment. Thus, there has been a shift in conceptualization away from “sec-
ondary insomnia” to the term “co-morbid insomnia.” The reasons for this shift
include: (1) the difficulty in accurately determining the cause of the sleep disturbance
or its misattribution, (2) the increasing recognition that even when a presumed cause
of insomnia is adequately addressed, significant sleep disturbance often remains,
and (3) in many cases the insomnia predates the comorbid disorder. In contrast to
co-morbid insomnia, primary insomnia is a term reserved for instances where
insomnia exists in isolation [5]. Co-morbid insomnia is most commonly observed in
medical practice and therefore is a key focus of this chapter.
Medical conditions that often occur in association with sleep disturbance
include arthritis, heart disease, hypertension, diabetes, stroke, cancer, breathing
disorders, and menopausal symptoms [6]. The most commonly occurring pulmo-
nary disorders that coexist with insomnia are COPD and asthma.
COPD, a slowly progressive condition causing inflammation in the small air-
ways and lungs [7], is frequently associated with dyspnea [2] and often leads to
fragmented sleep with frequent arousals due to both respiratory stimulant medica-
tions such as the methylxanthines, as well as the underlying disease processes [8].
In one population-based study, 32.1% of patients with COPD reported difficulty
falling asleep and 47.3% also reported frequent awakenings [6]. These reported
sleep difficulties are significantly greater than those without COPD and similar to
those with heart disease and neurological disorders [6]. In clinical samples more
than 50% of patients with COPD report at least some insomnia symptoms [2]. In
terms of having an insomnia disorder, 24.7% of patients with COPD met criteria
for an insomnia diagnosis, compared with 9.9% of those without the disorder [9].
There are minimal differences in objective measures of sleep with patients with
COPD having similar sleep latency and sleep efficiency (SE) compared with con-
trols [9]. However, those patients who meet the diagnostic criteria for insomnia
had a mean SE of 75.5%, significantly less than controls or patients with COPD
not meeting diagnostic criteria. This emphasizes the fact that COPD is more likely
to be a trigger for insomnia in vulnerable individuals rather than the cause of
insomnia. Furthermore, the finding that sleep disturbance becomes more severe
with advancement of the disease [10] emphasizes the importance of taking a com-
plete sleep history from patients with COPD and considering polysomnography
(PSG) particularly in those who may be at high risk for a sleep-related breathing
disorder or to document the severity of sleep disturbance using objective measures
[8]. It also raises the question as to the impact of insomnia on COPD severity. In
terms of asthma, one recent population-based study found that 26.7% of patients
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 235

with asthma reported often having difficulty falling asleep and 37.7% also reported
frequent awakenings [6]. The prevalence of patients with asthma meeting criteria
for insomnia is only slightly higher at 15% than the general population prevalence
of 10.1% [9]. Laboratory measures show their SE and sleep latency to be within
the normal range (86.73 ± 14.6). Even in samples of patients with asthma where
those with insomnia were compared to those without insomnia, minimal poly-
somnographic differences (sleep latency = 29.7 min ± 3.8 vs. 26.1 min ± 1.4;
SE = 83.6% ± 1.9 vs. 84.0% ± 0.4) were found [9]. It is possible that brief arousals
from sleep in patients with asthma may go undetected using traditional PSG or
that more severe sleep disturbance may be present in a subset of patients with
asthma who are untreated or are particularly severe. Future research in this area is
warranted examining both objective measures and insomnia-related symptoms
across a range of asthma severity and treatments using non-traditional measures
of sleep continuity.
Despite the strong association between insomnia and medical conditions, the
most prevalent co-morbidity is with psychiatric disorders, most commonly depres-
sion. In several large-scale prospective studies, insomnia is a significant risk factor
for the future development of depression [11–13]. Although the directionality
between insomnia and mental conditions, such as depression, has been debated,
insomnia can clearly be viewed minimally as a prodromal risk factor for depres-
sion. Within sleep clinics, insomnia comorbid with a mental disorder is the most
common comorbidity and is more prevalent in middle aged populations and in
women [14]. Insomnia is also one of the first reported symptoms of a mental dis-
order, and even after a depressive episode, sleep disturbance is among the most
common residual symptoms [14]. Both pharmacological and behavioral treat-
ments of insomnia have been shown to augment the antidepressant response of
SSRIs. However, research is needed to determine if continuing improvement
in insomnia can prevent relapse of depression. Finally, long-term longitudinal
studies are needed to determine if treatment of insomnia can prevent incident
depression. Nonetheless, as insomnia is often under-diagnosed and under-treated,
the link between insomnia and mental disorders emphasize the need for clinicians
to identify and appropriately target insomnia symptoms as well as the primary
condition is particularly important in the treatment of patients with pulmonary
diseases as they have been shown to have a higher prevalence of depression.
Appropriate psychiatric evaluation is a necessary component in evaluating any
patient with insomnia.
Insomnia can typically be managed effectively by the primary care physician.
However, sleep disturbance is also a common presenting symptom in patients
with other primary sleep disorders such as restless legs syndrome, sleep-related
breathing disorders, and periodic limb movement disorder [15]. Thus, it is impor-
tant for non-sleep specialists to be able to identify patients who are at high-risk for
these conditions and provide appropriate therapeutic intervention and/or referral
for a sleep evaluation.
236 C.E. Gargaro et al.

Table 13.1 DSM-IV-TR diagnostic criteria for primary insomnia

The predominant complaint is difficulty initiating or maintaining sleep, or non-restorative sleep, for
at least 1 month
The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or
impairment in social, occupational, or other important areas of functioning
The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-
related sleep disorder, generalized anxiety disorder, a delirium
The disturbance does not occur exclusively during the course of another mental disorder (major
depressive disorder, generalized anxiety disorder, a delirium)
The disturbance is not due to the direct physiological effects of a substance (drug abuse,
medication) or a general medical condition
From American Psychiatric Association [71], copyright 2000, with permission

DSM – IV

The DSM-IV defines primary insomnia as follows: (1) a complaint of difficulty

initiating or maintaining sleep or non-restorative sleep that persists for greater than or
equal to 1 month; (2) clinically significant distress or impairment in social, occupa-
tional, or other important areas of daytime function for which causation from other
sleep, medical, and psychiatric disorders is ruled out; (3) the sleep disturbance must
not occur exclusively during another sleep or mental disorder and is not due to the
physiological effects of a substance or a general medical condition (Table 13.1).
Individuals with insomnia often report more than one nocturnal symptom and also
vary in type, frequency, and severity of the symptom. It is important to note that, the
specificity and severity of the insomnia symptom can vary during the clinical course.

ICSD – II

In the International Classification of Sleep Disorders [16], all insomnias are

appropriately grouped together as a distinct sleep disorder category with different
variants [16]. Each subtype must meet the following criteria: (1) adequate sleep
opportunity (historically), (2) persistent difficulty sleeping (initiation, duration,
consolidation, or quality), and (3) associated clinical dysfunction such as fatigue,
attention deficits, memory impairment, mood disturbance, reduced motivation, or
excessive worrying [16].
Frequency, severity, and chronicity are all important dimensions of insomnia.
However, their importance in terms of diagnostic or therapeutic guidance has been
debated along with quantitative cutoffs used to make a diagnosis or categorize
severity [17]. A majority of insomnia clinical trials have defined insomnia with
sleep-onset or maintenance symptoms occurring three nights per week with the
criterion of 30 min or more for sleep initiation and 45 or more minutes for the
amount of wake time after sleep onset [17, 18].
Edinger et al. used sleep log data to determine the optimal frequency and
severity criteria that differentiates patients with insomnia from normal sleepers.
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 237

A relationship was found between severity and frequency of insomnia where the
optimal frequency criteria decreased as the symptom severity increased and vice
versa. Therefore, as both are clinically significant, a clinician could choose to
diagnose based on a higher frequency (e.g., ³3 nights per week) and lower severity
(e.g., <30 min), or a high severity (e.g., ³60 min) and low frequency (e.g., 1 night
per week). For example, a report of greater than 20 min for sleep latency occur-
ring four or more nights per week was similar in predictive value compared with
a sleep latency of 60 min or more once per week. Nonetheless, one should be
cautious in the sole use of specific quantitative sleep parameter criteria for
insomnia diagnoses as daytime impairment criteria have been underutilized and
clinically underemphasized both in terms of determining insomnia severity as
well as therapeutic efficacy [18]. Thus, an alternative approach would be to
determine appropriate sleep symptom severity in relation to the degree of
daytime impairments. An interesting line of inquiry in relation to quantitative
criteria, which deserves further exploration, is whether such criteria remain stable
across time and different relative to some other insomnia phenotype. For example,
person A has severely disturbed sleep once per week, while person B has
moderate-to-mild insomnia every night. If insomnia phenotypes such as this exist,
it is important to explore their relationship to morbidity. Large-scale studies are
needed in order to define appropriate quantitative criteria for these insomnia
symptom domains.
There are a few longitudinal studies concerning the course and duration of
insomnia. One 10-year longitudinal study utilizing 2,602 men aged 30–69 con-
ducted from 1984 to 1994 found that the prevalence of insomnia increased with
negative lifestyle factors and medical disorders [19]. The prevalence of insomnia
had increased over 10 years; however, the increase was most noticeable in the 30–40
year old age group. Of 266 with insomnia in 1984, 44% continued to report insomnia
symptoms in 1994, emphasizing the chronic nature of this disorder [19].
Assessing duration in insomnia is a critical component in the diagnosis of an
insomnia subtype. Acute insomnia, for example, has an identifiable stressor and is
relatively short in duration, typically lasting a few days to a few weeks and no
longer than 3 months. This type of insomnia has clear specific stressors, which can
be psychosocial, psychological, physical, or environmental, and includes difficulties
with interpersonal relationships, occupational stress, loss and bereavement, a new
medical disorder, or relocation. These individuals will most likely complain of
daytime sleepiness or fatigue as an important symptom [16]. The 1-year preva-
lence of transient insomnia is 15–20% for adults [16], the most common individuals
being women and older adults. Associated symptoms include sleep disturbance
(primary feature) as well as worry, anxiety, sadness, depression, physical symp-
toms, impaired concentration and irritability attributed to either the stressor or the
sleep disturbance. Alcohol, drugs, or self-medicating, worrying and poor sleep
practices can further perpetuate the symptoms. PSG is not routinely necessary for
a diagnosis of insomnia. When present, PSG measures may show prolonged sleep
latency, increased number and duration of awakenings, short sleep time, and
reduced SE [9, 16].
238 C.E. Gargaro et al.

Prevalence and Risk Factors of Insomnia

Insomnia is a common condition, with a prevalence of occasional or intermittent

insomnia at 30–40% of the general population and chronic insomnia at 10–15%
[20–23]. However, differences in diagnostic criteria influence prevalence data.
Daytime consequences are of great importance, and with this criterion included,
insomnia prevalence may be less [22]. Rates of insomnia are much higher in both
psychiatric and clinical populations, as previously discussed, and exceeds 50% in
selected populations (e.g., major depressive disorder) [23, 24].
The prevalence of insomnia is higher in women compared with men [25]. A meta-
analysis investigating sex differences has shown that insomnia is approximately 1.4
times more common in women and this ratio increases with age. This may be
accounted for by several factors: menopause, menstrual problems, and higher rates
of medical co-morbidities associated with insomnia (e.g., depression and pain disor-
ders). For example, in a National Health Interview Survey, it was found that among
women aged 18–55, 31% who had menstrual-related problems had insomnia [26].
Studies regarding the effects of race on insomnia risk have found that older age-
matched African Americans have less prevalent insomnia symptoms when com-
pared with European Americans, but this trend is reversed in the college age group
[27]. This relation between age and race is complicated by additional findings in
which a higher prevalence of insomnia symptoms among US-born African
Americans than among the Caribbean-born African Americans [28], and that there
may be a higher incidence among older African American women (19%) than men
(12%) and European Americans (14%) [29]. These results suggest that the influence
of race on insomnia risk is complicated by a variety of factors including age,
co-morbidities, sex, and socioeconomic status [30].
Sleep disturbance in childhood may result from sleep-related breathing disorders,
parasomnias including nocturnal enuresis, sleep walking, and sleep disorders related
to medical conditions or medications. However, the prevalence of insomnia in children
is unknown. A large-scale study found higher prevalence of insomnia in adolescent
girls (age range 11–14 years) compared with boys [31]. This finding implicates the
onset of the menstrual cycle [32] as a contributing factor. The association between
menses onset and insomnia might also be explained by hormonal changes in the
levels of testosterone and estrogen (Angold 1998, Refs. 41–44 in Johnson et al.
[32]). Insomnia is also more prevalent among adolescents aged 13–16 compared
with younger groups and the risk for insomnia was higher in girls than in boys, but
only after the onset of menses [32]. Among adolescents with sleep difficulties, the
most common complaints were difficulty initiating sleep (68.5%), non-restorative
sleep (48.1%), and difficulty maintaining sleep (26.2%). The onset of menses in
girls created 2.75 times increased risk for insomnia. The relationship between
insomnia and pubertal development is complex because of biological and social
changes that occur at the time of menses [32].
Aging is associated with sleep fragmentation, increased arousals, and more
frequent awakenings. Individuals over the age of 65 are more likely to report
fragmented sleep, difficulty falling back to sleep after nocturnal awakenings,
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 239

frequent early morning awakenings, and non-refreshing sleep [33]. Insomnia is also
more prevalent and complex in the elderly. The prevalence of chronic insomnia
increases from 25% in the adult population to 50% in the elderly [34]. Data from the
National Sleep Foundation shows that, 67% reported experiencing one or more
sleep problem, and 48% reported at least one insomnia symptom at least a few times
per week [35]. In the elderly, insomnia complaints are also more common in women
[36]. Insomnia in the elderly is associated with significant daytime conse-
quences, including increased risk of cognitive impairment, increased fall, and higher
mortality risk.
More than 1/3 of adults over the age of 65 fall each year, making falls one of
the leading causes of injury-related deaths [37] and the most common cause of
injuries and trauma-related admission to hospitals [38]. Falls can result in hip
fractures which limit mobility and function [39]. Previously it was thought that
hypnotic use for insomnia was a significant predictor of falls. However, it is now
known that insomnia produces a 90% increased risk for falls, as compared with
hypnotic use which is associated with a 29% increased risk [40]. Medication use
is one of the most significant causes of falling, with benzodiazepines (especially
those used during the day), sedative-hypnotics, cardiac medications, antidepres-
sants, neuroleptics, and use of multiple medications simultaneously being associ-
ated with increased risk of fall. This must not be overlooked because complications
include fractures of the wrist, hip, vertebrae, or subdural hematoma [41].
Physicians should be cautious of medications that may increase the risk for falls,
such as long-acting hypnotics (half life >6 h), where residual effects are more
prominent and in turn lead to slower response times and balance problems well
into the wake period [36].
In a study focusing on mortality risk, a 2-year follow-up on hospitalized geriatric
patients found that the presence of insomnia symptoms and specifically sleep onset
delay was associated with a higher mortality rate, indicating that insomnia may be an
independent risk factor for survival [42]. Insomnia and difficulty initiating sleep
have also been associated with coronary artery disease mortality in men [43].
Additionally, a study by Leppavuori et al. [44] found the prevalence of post-stroke
insomnia complaints to be 56.7% in a population of 486 stroke patients aged 55–85.
Given that the consequences of a stroke disable an individual and insomnia can
further debilitate daytime functioning, insomnia complaints should be taken seri-
ously and treated independently in medically ill patients.

Pathophysiology of Insomnia

Insomnia is often conceptualized as an underlying predisposition with precipitating

and perpetuating factors. Precipitating factors trigger insomnia in vulnerable indi-
viduals while perpetuating factors maintain the insomnia even after the trigger has
dissipated. This is termed the 3-P model of insomnia, developed by Spielman in
1986. Ultimately, optimal treatment involves identifying and addressing each facet
of the disorder.
240 C.E. Gargaro et al.

In terms of the predisposition to insomnia, Drake and Roth have hypothesized

that an important aspect of vulnerable individuals is pre-morbid sleep-reactivity to
stress [45]. Sleep reactivity is a term used to delineate an elevated response of the
sleep system to challenges known to disturb sleep. Over the past decade studies
have found increasing support for this hypothesis. For example, a measure of sleep
reactivity (Ford Insomnia Response to Stress Test) has been shown to predict the
degree of sleep disturbance (both PSG and self report) to diverse challenges, such
as a first night effect in the sleep laboratory [46] and the disruptive effect of low-
dose caffeine administration [45]. Reactivity is higher in insomniacs [47] and has
been shown to display substantial familial aggregation [48]. More recently a pre-
liminary analysis of sleep reactivity using a large twin cohort has shown a signifi-
cant genetic component providing evidence for more than 30% heritability of sleep
reactivity [49]. Additional studies investigating the predictive value of sleep reac-
tivity are needed before definitive conclusions regarding this potential predisposing
factor can be made.
Regardless of the exact nature of the predisposition, the interaction between
triggers and vulnerability may cause certain individuals who experience stressors
to have an increased sleep response in terms of magnitude, duration, and/or fre-
quency which eventually leads to insomnia [45]. Onset of insomnia can be triggered
by many different medical, psychiatric, psychosocial, or environmental factors
[50]. Several psychosocial stressors, including marital difficulties, divorce, separa-
tion, and dysfunctional relationships within the family have been linked to the onset
of insomnia [50]. Work-related sources of stress that were identified as precipitating
insomnia included conflicts with a supervisor, interpersonal relationships, work-
load, and financial strain. A vicious cycle may develop whereby stress at work
develops into disturbing and intrusive thoughts when a person is trying to sleep and
is unable to relax. This stress may also be cumulative, where sleep problems are
produced only after the accumulation of stress over time. Ongoing financial strain
has been measured as a form of chronic stress and has shown significant importance
in the elderly population [51]. Persistent financial strain was associated with sleep
continuity disturbances in a sample of community elders between the ages 61 and
85. Elders experiencing ongoing financial strain took longer to fall asleep, and had
an average of 88 min of wake after sleep onset (WASO), as compared to 69 min
among elders who did not self-report financial strain. While precipitating events
have been shown to vary with age, they are fairly consistent across genders [50].
Age of insomnia onset was related to different categories of precipitating factors;
precipitants related to work and/or school were more common when the onset of
insomnia occurred earlier in life, whereas health factors were associated with
insomnia later in life.
Maladaptive behaviors such as poor sleep habits, cognitive arousal, ruminating,
worrying, or catastrophizing often serve to maintain the insomnia despite the disap-
pearance of an initial precipitating factor [13]. For example, insomnia could be
maintained by habits such as inappropriate caffeine or alcohol consumption,
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 241

increased time in bed, napping, or other poor sleep hygiene practices, even after
the precipitating stimuli has been removed. One study has shown that individuals
with insomnia are more likely to engage in inappropriate sleep practices that may
exacerbate or perpetuate sleep disturbances [47]. These behaviors include smoking,
alcohol use, and compensatory sleep (naps and sleeping in on the weekends). Not
only was the prevalence of smoking and alcohol use higher in insomniacs com-
pared with controls, but insomniacs were also more likely to smoke within 5 min of
bedtime and use alcohol to induce sleep within 30 min of bedtime. Some insom-
niacs choose to self-medicate with alcohol in order to induce or improve their
sleep and of these 67% perceived it as effective in alleviating symptoms, consistent
with the widespread inappropriate use of alcohol to help sleep [52]. This may lead
to an increased risk of dependence and tolerance requiring larger amounts of
alcohol in order to reach similar effects on sleep [53]. However, alcohol fragments
sleep, particularly during the second half of the night [54]. Such fragmentation may
not be detected by the individual. Compensatory daytime napping may become a
factor, which decreases an individual’s homeostatic sleep drive at night, subse-
quently producing sleep disturbance. Insomniacs have been shown to “sleep in”
more frequently, possibly as an attempt to compensate for their disturbed sleep at
night [47].

Clinical Assessment

Sleep History

It is important to determine whether the patients’ habits are contributing to their

insomnia. A physician should determine usual work hours, and whether the
patient spends appropriate time in bed relative to sleep time. A two-week sleep
diary is one of the best ways to have a patient keep track of their bedtimes, wake
times, quantity and quality of sleep, as well as other factors such as alcohol, tobacco,
and medication use. The National Sleep Foundation is a resource where a sleep
diary can be found for clinical and research use (www.sleepfoundation.org).
Spending enough time in bed may improve sleep, considering no other pathologies
are present [55]. However, in most cases, patients with insomnia are unable to
attain 7–8 h of sleep despite adequate time in bed and spending too much time in
bed further fragments sleep. Prescription drugs, pain medications, alcohol, and
caffeine can all disrupt normal sleep and complicate the diagnosis [55]. It is impor-
tant to ask the patient about their sleep environment and any other factors that could
be interfering with their sleep such as excessive cold, heat, light, or noise. Other
clinical questions are also useful including: does a patient take naps and as a result,
feel more alert? What types of settings cause them to doze? [56, 57].
242 C.E. Gargaro et al.

Medical History

In terms of pulmonary conditions, patients with COPD often present with the
complaint that their sleep is fragmented and they have difficulty falling back to
sleep. Their PSGs have shown increased time in stage 1 sleep, increased arousals,
and decreased REM, often related to hypoxemia or hypercapnic events.

Psychiatric History

It is important to be aware of potential psychological disorders especially depres-

sion and anxiety, which often present co-morbidly with insomnia. Psychological
stress has also been shown to play a significant role in the onset and maintenance of
primary insomnia in adolescents, and young adults [55]. To help in identifying
patients who have personality disorders, a screen for psychological disorders can
be used. A drug screen is also important in ruling out drug abuse which may have
profound effects on sleep [56, 57].

Family History

It is suggested that patients who have insomnia have a higher incidence of relatives
with sleep disturbances, with the mother most commonly affected. It is very impor-
tant to discern whether there is any family history of insomnia or medical or psychi-
atric disorders to understand all familial factors surrounding the disorder as an
indicator of potential underlying predisposing factors. Of equal relevance are the
patient’s psychosocial history, occupational and school performance, amount of
interpersonal support, and presence of psychosocial stressors, all of which can
precipitate insomnia [56]. A patient’s significant other is also a valuable resource
for information about their bed partner’s symptom frequency, duration, severity, and
daytime impairment as well as the presence of breathing problems, periodic limb
movements, or parasomnias during sleep.

Medication History

Many different medications can contribute to sleep complaints and daytime conse-
quences. A thorough assessment of all prescription and non-prescription medica-
tions, CNS stimulants (including many weight loss supplements), and herbal
remedies can play a significant role in perpetuating or exacerbating the insomnia.
Prescription medications used to treat COPD, asthma, allergies, hypertension,
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 243

epilepsy, psychotic disorders, anxiety, and pain if present should be important

considerations in the evaluation [57, 58]. A physician needs to assess the dosage,
type, frequency, and timing of usage and consider the timing of onset of insomnia
complaints in order to determine whether continued use is necessary or timing of
dosing can be modified to minimize the sleep disruptive effects of the medication [56].
A significant portion of the insomnia assessment and interview should be focused
on the evaluation of medical disorders, psychiatric conditions, other sleep disorders,
and substance use, all of which are commonly co-morbid with insomnia. This will
help determine whether the identified complaint and condition is a predisposing,
precipitating, or perpetuating factor.
Different types of behavioral insomnia treatments include relaxation therapies,
stimulus control, sleep restriction, paradoxical intention, improving sleep hygiene,
and cognitive behavioral therapy. There are also pharmacological treatments for treating
the co-morbid insomnia conditions. Cognitive–behavioral insomnia treatment and
pharmacotherapy with benzodiazepine receptor agonists have both been proved
effective [30, 59]. Please refer to Chapter 15 in this volume for further information.
As insomnia is a symptom-based diagnosis, PSG is usually not necessary.
However, PSG is useful if there is suspicion of another primary sleep disorder, such
as apnea sleep-related breathing disorder. Individuals with chronic insomnia may
still have PSG sleep that is within normal limits (>85% SE and <30 min sleep
latency). Therefore, polysomnograms are most important in ruling out obstructive
sleep apnea, periodic leg movements, and other primary sleep disorders in patients.
Self-reported measurements of sleep are effective, take minimal time, and are
useful in a variety of medical settings. Sleep diaries are considered a standard self-
reported measure of insomnia with a recommended collection time of two weeks in
order to obtain reliable information regarding sleep patterns. Sleep diaries typically
include sleep onset latency, time of awakening during the night after sleep onset
(WASO), number of awakenings during the night, total time in bed (TIB), total
amount of sleep (TST), and SE calculated from TST/TIB as a percentage. Estimates
of naps, types of medication, caffeine, alcohol, nicotine use, and ratings of sleep
quality can be included. A sleep diary is especially valuable when a circadian rhythm
disorder is thought to be comorbid with the insomnia. Insomnia severity scales such
as the insomnia severity index can help the clinician asses the severity of the insom-
nia as well as the effectiveness of the treatment [60].
When objective measures of sleep are desired in patients with insomnia, one
useful method of assessing sleep is actigraphy, which is a small movement activated
device attached to a patient’s dominant wrist [61]. The algorithm of movement and
non-movement has been shown to predict PSG within 93% accuracy for normal
subjects. Minutes of non-movement are recorded as sleep time and SE reported as
minutes of non-movement divided by TIB. Actigraphy has also been shown to detect
changes in sleep variables in response to treatment, and may be more accurate than
sleep diaries due to its promotion of treatment compliance at home and high reli-
ability [62]. Thus, actigraphy can be a useful tool for assessing habitual sleep
patterns as well as night-to-night variations in sleep. However, the accuracy of sleep
onset calculated by actigraphy has been questioned; as individuals lie motionless in
244 C.E. Gargaro et al.

bed actigraphy may score wake as sleep. Thus, caution should be used when
evaluating this measure based on actigraphy alone. Actigraphy in determining sleep
onset has been questioned and caution in evaluating latency is warranted, as indi-
viduals my lie motionless in bed where actigraphy may inaccurately score wake as
sleep [62].

Functional Outcomes Associated with Insomnia

Sleep plays a vital role in the regulation of endocrine functions and glucose metabo-
lism. Reduced sleep duration and/or poor quality sleep may be linked to an increased
risk for diabetes mellitus and insulin resistance [63]. Insomnia with short sleep
duration (<5 h) has also been associated with increased risk of hypertension
(OR = 5.12 and 95% C.I. 2.2–11.8) [64]. Therefore, insomnia in combination with
short sleep appears important in terms of cardiovascular risk [64]. The ability to
consolidate newly encoded memory traces during sleep is also reduced in patients
with insomnia [65]. Additionally, primary insomnia is associated with decreased
sleep-related consolidation of declarative memory [66]. In terms of quality of life,
studies have shown higher divorce rates, reduced job satisfaction [67], and reduced
family and social interaction among people with insomnia [68]. In a study by Leger
et al. [67], insomniacs had an almost twofold higher rate of absenteeism as com-
pared to normal good sleepers; as measured during a 2-year period, 50% of insom-
niacs and 34% of good sleepers had an absence during this time. Insomniacs also
have higher rates of hospital and medical services utilization, including visits to
healthcare professionals, medical examinations, medications, and hospitalizations
[67]. The individual cost to society has been estimated at $552 per year in work-
related absences and $4,154 in reduced productivity [69], with direct and indirect
costs exceeding 30 billion annually [1, 70]. Notably, the costs of untreated insomnia
are significantly greater than the direct costs associated with treatment. Leger
et al. [67] also found that the annual loss of insomnia-related productivity is 27.6
days per year vs. 2.8 days for good sleepers, a 10:1 ratio. Finally, insomniacs have
been found to have a higher incidence of major accidents, are less likely to report
being responsible for the accident, and report longer absences after the accidents
as compared to good sleepers [67].

Conclusion

Insomnia is a common and complex disorder, arising from a multitude of psychoso-

cial and biological factors. It is under recognized in medicine and yet is significant
in terms of the consequent health effects, quality of life, social, occupational, and
mental health components [71]. Insomnia is also associated with an increased risk
for psychiatric illness and other adverse health problems, increased falls and
13 Insomnia: Etiology, Clinical Manifestations, and Morbidity 245

accidents, greater healthcare utilization, and overall costs to society. In the clinical
setting, there is a need to standardize the assessment instruments, diagnostic criteria
and evaluation strategies. The initial identification and management of insomnia
would be greatly improved by the increased use of validated brief assessment tools,
outcome measures, and algorithms for treatment within and outside the sleep clinic
and pulmonary care settings.

Summary of Keypoints

• Insomnia is a serious public health concern with a high prevalence of co-morbid

conditions and serious societal and health consequences.
• Many pulmonary conditions produce sleep disturbance and may contribute to
the development of chronic insomnia in predisposed individuals.
• Affects women approximately 40% more than men.
• The pathophysiology of insomnia includes Spielman’s 3-P Model, the interac-
tion between predisposition, precipitants, and perpetuating factors and maintaining
factors.
• Maladaptive behaviors include caffeine and alcohol consumption, poor sleep
hygiene habits, and their association with reduced and fragmented sleep.
• Assessment of a patient with insomnia should include a sleep history, medical
history, psychiatric history, family history, and the use of self-reported measures
such as a sleep diary.
• Negative functional outcomes associated with insomnia can occur in terms of
memory, absenteeism, and productivity.

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71. Sateia MD. Description of insomnia. 2nd ed. New York: Informa Healthcare USA, Inc.;
2009.
72. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th
ed., Text rev. Washington: American Psychiatric Association; 2000.
Chapter 14
Management of Insomnia

Luisa Bazan, Thomas Roth, and Christopher L. Drake

Keywords Neuromuscular disorders • Insomnia • Interstitial lung disease • Chronic

obstructive pulmonary disease • Asthma • Nocturnal hypoxemia • Hypnotics

Introduction

Insomnia is defined as a “subjective report of difficulty with sleep initiation, duration,

consolidation, or quality that occurs despite adequate opportunity for sleep, and that
results in some form of daytime impairment” [1]. It is one of the eight major cat-
egories of sleep disorders in the International Classification of Sleep Disorders,
second edition (ICSD-2) [2]. Symptoms of insomnia may occur in association with
comorbid disorders or other sleep disorders, such as sleep-related breathing dis-
orders, circadian rhythm sleep disorders, and sleep-related movement disorders
[1, 3]. However, it is increasingly recognized that insomnia is a primary disorder
and independent treatment of the sleep disturbance is warranted even in the context
of other common comorbidities such as depression or respiratory disorders [4].
According to population-based studies, more than 30% of adults report sleep
disruption, while approximately 10–20% have associated symptoms of daytime
impairment or distress consistent with the diagnosis of insomnia [5, 6]. It is estimated
that the majority of people with insomnia (approximately 75–90%) have comorbid
medical disorders, such as conditions causing hypoxemia and dyspnea, gastroe-
sophageal reflux disease, pain conditions, and neurodegenerative diseases [3, 7, 8].

L. Bazan • T. Roth • C.L. Drake (*)

Sleep Disorders and Research Center, Henry Ford Hospital,
2799 W Grand Boulevard, Detroit, MI 48334, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 249
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_14,
© Springer Science+Business Media, LLC 2012
250 L. Bazan et al.

It has been reported that insomnia with objective short sleep duration is associ-
ated with a significantly increased risk for hypertension and type 2 diabetes [9, 10].
Studies have also shown increased mortality in males with insomnia symptoms and
objective short sleep duration (less than 6 hours of sleep) [11]. Based on this infor-
mation, it is possible to infer that patients with respiratory disorders, such as chronic
obstructive pulmonary disease (COPD), with comorbid insomnia, are at higher risk
for developing hypertension and diabetes and worse mortality.
Meissner et al. evaluated the prevalence of sleep complaints in a group of general
medical patients admitted to a Veterans Affairs tertiary care medical center. A total
of 222 consecutive adults completed the questionnaire. Of these, 105 patients (47%)
reported either insomnia, excessive daytime somnolence, or both. Of 75 patients
(34%) who reported insomnia, a third were taking hypnotic medication. Despite
this, none of the patients with insomnia had any mention of the sleep difficulties in
their medical record [12]. This study demonstrates that physicians in general, often
fail to ask patients about their sleep. Not doing so increases the risk of missing sleep
disorders where effective treatment could have the potential to improve overall
prognosis and quality of life.
This lack of attention to sleep disorders can be traced back to medical school
curricula. A national survey conducted by Rosen et al. in 126 accredited medical
schools in the United States showed that less than 5% of medical schools offer 4 or
more hours of didactic teaching on sleep, most of which consists of fourth year
elective experiences. More than two-thirds of the survey respondents stated that
current sleep education is inadequate and that additional time should be devoted to
this area [13]. These studies emphasize the rationale for education regarding the
treatment of insomnia in pulmonary settings.
Treatment of insomnia can be challenging, particularly when multiple comor-
bidities are present. Cognitive behavioral therapy (CBT) with or without concomi-
tant pharmacologic therapy is recommended [1]. Although most pulmonologists are
adept at treating OSA, adequate expertise to treat insomnia, especially behavioral
approaches, may be limited. Sixty physicians participated in an interactive survey at
the 1998 American College of Chest Physicians (ACCP) annual meeting.
Performance on test questions about sleep-related breathing disorders was better
than on questions about “non-breathing related” sleep disorders. The respondents
recognized a need for supplemental training, familiarity with the technical aspects
of sleep medicine, and access to other specialists in the field [14]. Thus, despite
extensive training in sleep-related breathing disorders, pulmonary physicians can
benefit from additional training on the diagnosis and treatment of non-breathing
related sleep disorders such as insomnia.
In this chapter, we will review the current data on pharmacologic and non-
pharmacologic treatments for insomnia focusing on the potential importance to
pulmonary medicine specialists.
14 Management of Insomnia 251

Control of Breathing During Sleep

Treating insomnia comorbid with respiratory disorders can be complex. Sleep in

patients with lung disease is affected by their pulmonary symptoms (e.g., cough,
shortness of breath), baseline hypoxemia, baseline hypercapnea, as well as medica-
tions utilized for the treatment of pulmonary disorders. The current treatment
modalities for insomnia include behavioral vs. pharmacological therapy. If pharma-
cological therapy is considered in a patient with an underlying pulmonary disorder,
it is important to have adequate understanding of the respiratory physiology during
sleep and the effects of the different therapeutic agents on control of breathing,
since patients with underlying lung disease have limited reserve to overcome further
challenges to ventilation during sleep.
In this chapter we will review the effects of hypnotic medications on the respira-
tory drive in relation to hypercapnea and hypoxemia and their effect on respiratory
muscle function.
Control of breathing is affected by the state of consciousness. During wakeful-
ness, the volitional control of breathing input from the waking state is an important
stimuli to the ventilatory function. However, volitional control of breathing is abol-
ished during sleep leading to decrease stimulation of respiratory drive. Positional
changes associated with sleep also result in alterations in respiratory mechanics.
Sleep has effects on breathing, including changes in respiratory control, airway
resistance, and muscular contractility [15, 16].
Sleep is subdivided into two distinct states: non-rapid-eye movement (NREM)
and rapid-eye movement (REM) sleep. Various aspects of respiratory control differ
between wakefulness, NREM and REM sleep. The reader is referred to Douglas
[17] for a review. For example, minute ventilation in healthy individuals falls during
sleep due to decreased metabolism and decreased chemosensitivity to carbon dioxide
(CO2) and oxygen (O2). The drop of ventilation between wakefulness and NREM
sleep has been shown to be between 10 and 15%. The drop of ventilation during
REM sleep has been calculated at 15–16% from the awake state [15, 18, 19].
CO2 is the most potent respiratory stimulus. The end-tidal CO2 (ETCO2) increases
by 2–3 Torr during NREM sleep with a further increase of 2–3 Torr during REM
sleep. Thus, the arterial carbon dioxide partial pressure (PaCO2) can be up to 5 Torr
higher in REM sleep than in wakefulness. The increase in PaCO2 should increase
minute ventilation during sleep; however, the opposite happens. There is actually a
decrease in the slope of the ventilatory response to increasing inspired CO2 during
sleep. That drop is modest during NREM sleep and is greater in REM sleep. These
changes are more evident in males than in females. Respiratory output in sleep,
particularly NREM sleep, is significantly reduced in response to hypocapnea. The
changes in chemosensitivity to PaCO2 can be related to peripheral mechanical fac-
tors or central neural factors [16, 19, 20].
252 L. Bazan et al.

In normals, both hypercapnea and hypoxia activate the sympathetic nervous

system and produce arousals. The arousal threshold for CO2 is typically between
55 and 65 Torr although there is a significant variation in that range [19]. During
sleep, an elevation of the ETCO2 of 15 mmHg above the level in wakefulness
awakens most subjects [21]. Douglas et al. evaluated hypercapneic drive during
sleep. The rise in CO2 during hypercapneic ventilatory responses (HCVR) was
significantly higher during wakefulness (12.7 ± 0.3 mmHg) than during sleep
(9–10 mmHg) with no difference between the mean rise in each sleep stage [20].
Berthon-Jones and Sullivan [22] reported CO2 arousal thresholds up to 6 mmHg
higher in slow wave sleep (SWS) than in either stage 2 or REM sleep in male but
not in female subjects.
The eucapnic hypoxia arousal threshold in healthy humans shows a marked
variability in NREM and REM sleep, with subjects failing to awaken by 70% of oxygen
saturation (SaO2). The wake-NREM and wake-REM ventilatory responses to hypoxia
were significantly different; however, the NREM–REM difference was not [23].
Pappenheimer noticed that acute exposure of rats to 10.5% O2 (5,030 m altitude equiv-
alent) during daylight hours (sleep phase) virtually abolished REM sleep and shifted
the distribution of amplitudes of SWS electroencephalography (EEG) toward awake
values. Similar disruption of sleep occurred during inhalation of 0.05% carbon
monoxide (CO) with steady-state carboxyhemoglobin of 35%. The decreased intensity
of NREM sleep during hypoxia (i.e., decreased amplitude of cortical slow waves),
may explain the disparity between subjective complaints of insomnia at altitude and
evaluations of sleep by direct observation or by conventional EEG [24].
Because some hypnotics suppress musculoskeletal function during sleep, and
these effects vary in intensity depending upon sleep stage, it is important to under-
stand the effects of changes in sleep state on upper airway and respiratory muscle
function. NREM sleep is associated with a decline in activation of the upper airway
muscles that is amplified during REM sleep. The activity of respiratory accessory
muscles in the neck and chest wall is inhibited during REM sleep. REM sleep
is subdivided into two periods: tonic and phasic. During REM sleep, there is tonic
absence of muscle tone (i.e., muscle atonia), but the phasic period is further identi-
fied by bursts of desynchronized REMs. During these bursts of REMs, the electrical
activity of the diaphragm is quite irregular and desynchronized, thus further con-
tributing to a reduced ability of this muscle to generate force [16]. Thus, REM
reduces respiratory muscle activity leading to hypoxemia and hypoventilation which
can be a significant contributor to sleep complaints (i.e., nocturnal awakenings) in
patients with respiratory disease.
Patients with underlying lung disease are also at risk for oxygen desaturation and
increased ventilation–perfusion mismatch as a result of sleep-related hypoventilation
and postural change, respectively. In response to this hypoxemia and/or hypercapnea,
ventilation and respiratory effort both increase. While the arousal response to hypox-
emia is not always consistent, when combined with an increased effort of breathing it
can produce arousals potentially leading to reports of disturbed sleep [25].
14 Management of Insomnia 253

Pulmonary Disorders and Sleep

Patients with pulmonary disorders often report insomnia-related symptoms. Studies

have evaluated the prevalence of insomnia as well as reports of sleep disturbances
in patients with different pulmonary disorders.

Bronchospastic Airway Disorders

Patients with bronchospastic airway disease frequently report difficulties with sleep.
Klink et al. reported the prevalence of sleep disturbances in a general adult population
and in a subgroup of patients with chronic obstructive airway disease in the Tucson
Epidemiologic Study. Patients were classified as having either asthma, chronic bron-
chitis alone or chronic bronchitis with asthma and emphysema. Subjects with chronic
bronchitis alone and emphysema had a 53.2 and 54.6% prevalence of difficulty initiat-
ing or maintaining sleep (DIMS) and 26.2 and 28.8% prevalence of excessive daytime
sleepiness (EDS), respectively, each of which was significantly higher relative to
those with no airway disease (35.6 and 10.6%). Patients with chronic bronchitis and
asthma showed the highest prevalence of DIMS (75%) and similar prevalence of EDS
(25.2%). In patients with asthma the prevalence of DIMS and EDS was no different
than in patients with no airway disease. No significant influence of smoking status
was noted in any of the four groups [26]. It has been consistently shown that patients
with asthma report disrupted sleep. Fitzpatrick found that 85% of asthmatics report
waking up at night with wheeze occasionally, and 31% did frequently (more than 20
times/year) [27]. Turner-Warwick et al. found that among primary care patients in the
United Kingdom, 74% of patients with asthma report awakening at night at least once
a week, and 64% reported awakening at least 3 times a week. Even in patients that
regarded their asthma as mild, 26% of them reported awakening every night [28]. In
a study with cystic fibrosis patients, with an average age of 14 years old, 43.5%
reported sleep onset problems, 39.1% reported sleep maintenance problem, 30.4%
were noted to snore at night, and 73.9% reported daytime sleepiness. On PSG evalu-
ation, sleep efficiency was decreased, REM latency was increased, and REM sleep
was decreased relative to controls. Sleep efficiency was correlated with forced expira-
tory volume in 1 s (FEV1) but there was no correlation with minimum oxygen satura-
tion or maximal ETCO2. The magnitude of sleep disruption in these patients was
mainly related to the severity of their lung disease, but not directly correlated with the
degree of nocturnal hypoxemia or hypoventilation [29].

Interstitial Lung Diseases and Sleep

Several studies have reported disturbed sleep in patients with interstitial lung
diseases (ILD) and Interstitial Pulmonary Fibrosis (IPF). Patients with ILD showed
254 L. Bazan et al.

more stage 1, less REM sleep, more arousals and sleep stage changes relative to age
and gender-matched controls [22]. Patients with awake oxygen saturation less than
90% had a higher percentage of stage 1, more sleep state changes, and longer awake
time than did patients with awake saturation above 90%. The apnea/hypopnea index
(AHI) in patients with ILD and controls was within normal limits in this study [30].
Krishnan et al. [31] found that mean scores on the Pittsburgh Sleep Quality Index
(PSQI) was significantly higher in IPF patients relative to controls, indicating poor
sleep in these subjects as compared to controls.
Mermigkis et al. studied 15 patients with IPF and 15 control subjects. There
were statistically significant differences between IPF patients and controls on PSG in
sleep efficiency (65% vs. 78%), stage 1 sleep (18.7% vs. 7.4%), SWS (10.4% vs. 16.5%),
arousal index (AI) (26 vs. 13 events/h), mean oxygen saturation (91.6% vs. 95.3%),
nadir oxygen saturation during sleep (81% vs. 91%), and the percentage of total
sleep time (TST) with oxygen saturation under 90% (34% vs. 0.9%). There was no
significant difference in the AHI (9.2 vs. 7.1 events/h). Daytime tachypnea persisted
during sleep (20.6 vs. 22.9 breaths/min (bpm), respectively). The most common
complaint was daytime fatigue, reported in all cases and also confirmed by the
Fatigue Severity Scale (FSS) scores. EDS, snoring, insomnia, and witnessed apneas
were reported in 20, 40, 46.6, and 13.3% of the cases, respectively. Quality of sleep
and daytime function were moderately to significantly impaired based on the PSQI
and Functional Outcomes of Sleep Questionnaire (FOSQ), respectively. Nocturnal
hypoxemia showed a significant correlation with FSS scores. The total FOSQ score
was negatively correlated with TST with oxygen saturation below 90%. FSS scores
were correlated with TST at oxygen saturation below 90% and mean oxygen satura-
tion during sleep. Thus, nocturnal hypoxemia appears to be associated with a reduc-
tion in energy levels and impairment of social and physical functioning [32].
As hypoxemia has been found to correlate with daytime fatigue and interruptions of
sleep at night, it raises the hypothesis that oxygen supplementation will improve sleep.
Vazquez et al. evaluated the impact of oxygen on patients with ILD. The average arte-
rial oxygen partial pressure (PaO2) was 51 mmHg while awake. All patients underwent
two consecutive full PSGs, one breathing room air and one breathing supplementary
oxygen through nasal prongs. Controls were studied for one night breathing room air.
The mean SaO2 in ILD patients was 82% during sleep on room air and 94.8% on oxy-
gen. In controls it was 92.9%. Sleep efficiency and AI were similar in patients and
controls and did not change with oxygen. Thus, hypoxemia does not appear to be the
cause of sleep disturbance in patients with ILD [33]. Another potential etiology of
disturbed sleep in these patients is the increase in respiratory frequency while sleeping.
This phenomenon has been attributed to the persistence during the sleep phase of the
reflexes causing the rapid shallow breathing during wakefulness. To the author’s knowl-
edge, the evaluation of that mechanism (rapid, shallow breathing) as a potential cause
of disturbed sleep has not been done.
Patients with IPF have poor prognosis and poor response to the current available
treatments. Dyspnea and coughing are usually progressive and about 50% of the
patients die within 3 years after diagnosis. The early recognition of sleep distur-
bances and its treatment should be one of the primary goals of care, since it may
improve quality of life in a disease with no effective treatment. Studies to evaluate
14 Management of Insomnia 255

the safety of hypnotics in this patient population are important yet, to date no studies
have assessed the efficacy or safety of hypnotics in this group. Other therapeutic
aspects of IPF symptoms such as cough with antitussive therapy; oxygen supple-
mentation or non-invasive ventilation on sleep and breathing should be evaluated in
controlled trials, having as a goal the improvement of sleep disturbance in these
patients. The response of insomnia symptoms to CBT in this population should also
be evaluated, since it can potentially be successful; CBT has been used in other
disorders with comorbid insomnia with good results. Potential limitations for the
application of CBT in this group of patients might be the progression and severity
of their disease. However, as in the case of hypnotics, the effects of sleep restriction,
one of the interventions used in CBT, and associated blunting of arousal with excessive
sleepiness needs to be evaluated.

Kyphoscoliosis, Restrictive Thoracic Cage Disorders, and Sleep

Guilleminault et al. studied five severe kyphoscoliosis (KS), with four of the five
having been referred to the sleep laboratory; two complained of severe daytime
sleepiness, one complained of disrupted nocturnal sleep, and one was referred for
concerns of obstructive sleep apnea (OSA). All the patients were found to have
apneas or hypopneas (AHI between 11 and 68) associated with desaturations [34].
Sawicka et al. studied 11 subjects with non-paralytic, 10 with paralytic KS, and 9
with normal controls. The sleep evaluation did not show any difference in TST or
REM percentage among the groups despite the differences in pulmonary parameters
such as rise in end tidal volume and transcutaneous CO2 and a reduction in oxygen
saturation especially during REM sleep in KS patients [35].
Masa et al. in a group of five patients with restrictive thoracic disorders (two of
them with only KS, two with KS associated to myopathy or spondyloschisis, and
one with history of thoracoplasty), found a 20% (one out of five patients) incidence
of insomnia after discontinuation of at least 2 months of successful non-invasive
positive pressure ventilation (NIPPV) therapy. Upon comparison of the sleep data
while on NIPPV and after withdrawal of NIPPV therapy, there was an increase in
the number of arousals and awakenings following withdrawal which can indicate
more disturbed sleep; however, the difference was not statistically significant
possibly due to the small sample. A severe worsening of gas exchange was observed
as well, mainly during REM sleep. The lowest oxygen saturation in REM sleep with
NIPPV was 74% and without it was 47%. Patients spent only 17 min on average
under 80% saturation while on NIPPV, and 212 min without NIPPV. It is possible
that the sleep disturbances in patients with KS are related to the hypoxemia secondary
to hypoventilation which is resolved by NIPPV [36].
Gonzalez et al. evaluated the effects of long-term NIPPV on symptoms, pul-
monary function test results, sleep and respiratory muscle performance in patients
with ventilatory insufficiency due to severe KS. Sixteen patients were included.
Although PSG results showed no significant differences in sleep stages, sleep
efficiency, number of arousals or awakenings, or TST after 6 months of treatment,
256 L. Bazan et al.

there was a significant improvement in symptoms of perceived sleep quality and

daytime drowsiness quantified using a visual analog scale (VAS) before and after
the initiation of NIPPV [37]. In another similar study by Brooks et al. an evaluation
of the long-term effects of home mechanical ventilation (HMV) on pulmonary
function, gas exchange, sleep architecture, and functional exercise capacity (6-min
walk test) was performed. Seventy-four patients with KS or neuromuscular disease
were included. Measurements were done upon initial evaluation before initiation
of HMV and immediately after. Measurements were repeated 1–2, 5, and 8–10
years later. There were no differences on sleep efficiency or AI after initiation of
NIPPV [38]. Both studies showed improvement in gas-exchanged parameters and
exercise performance, respectively after initiation of NIPPV on this population.
There was also an improvement in the perception of sleep quality in the first study,
even though there were no changes on the sleep parameters measured by PSG, even
after 10 years on NIPPV. It is possible that the poor perception of sleep quality
was not related to abnormalities in the sleep pattern evaluated by PSG, but mainly
to the abnormalities in gas exchanged which were improved on NIPPV. Based on
that finding, NIPPV should be considered the first-line therapy for patients with
KS with poor sleep quality. The studies mentioned above do not categorize the
sleep complaints as either sleep initiation or sleep maintenance problems. This is
unfortunate since addressing that issue can help in deciding the most adequate
pharmacologic therapy.
No studies have been done in this population to evaluate the effects of pharma-
cological treatment for insomnia or the safety profile of hypnotics, or other pharma-
cologic agents such as ramelteon or doxepin. The use of sedative hypnotics can be
of concern due to their potential worsening of their already very limited pulmonary
function. For example, patients with KS develop shallow breathing to counteract the
increased work of breathing secondary to their abnormal lung mechanics.
A subsequent blunting of the ventilatory response to hypercapnea develops as well.
The lower tidal volume results in increased dead space ventilation. Reduced lung
volumes are associated with the closure of small airways, abnormal distribution of
inspired air, and atelectasis, which all contribute to hypoxemia. Low functional
residual capacity puts the patient at risk for more rapid desaturations with any level
of sleep disordered breathing (SDB). Patients with KS also develop problems with
control of breathing such as in patients with a history of poliomyelitis, whose dis-
ease affects the medullary centers in addition to the respiratory muscles [39]. If
patients with KS develop insomnia, a very good option will be CBT since that can
potentially be successful and avoids the use of pharmacological therapy. If pharma-
cologic therapy is decided, doxepin or ramelton, due to their mechanisms of action,
are less likely to produce worsening hypoxemia or hypoventilation, so they might
be considered safer in this population. It is unclear if they will be effective, however,
since no studies in this population have been published. If sleep initiation is the
main complaint, then ramelteon would be a good option; if the problem is sleep
maintenance, then doxepin will be the alternative. Both options should be evaluated
in future studies.
14 Management of Insomnia 257

High Altitude Sickness and Insomnia

Current transportation technology allows millions of people a rapid ascent to high

altitudes for travel or recreation. In unacclimatized persons, failure of the body to adapt
to the stress of hypobaric hypoxia may lead to cerebral and pulmonary syndromes
as well as insomnia.
Acute Mountain Sickness (AMS) and High-altitude cerebral edema (HACE)
refer to the cerebral disorders, while high-altitude pulmonary edema (HAPE) refers
to the pulmonary abnormalities. Risk factors for developing high-altitude illness
include ascending too rapidly the length of altitude exposure and acclimatization,
absolute height of altitude, increased level of exertion, increased obesity, cold tempera-
ture, low pressure weather systems, increased fitness level, and personal physiologic
susceptibility [40, 41].
Alterations in sleep quality have been reported at high altitude. Szymczak et al.
evaluated sleep quality at high altitude using the PSQI and the Athens Insomnia
Scale (AIS-8) in an expedition conducted in the Himalayas (4,524 m). PSQI scores
showed that 17 (53%) of the participants experienced poor sleep quality and according
to the AIS-8 criteria for insomnia cutoff score, there were 15 (47%) insomniacs.
In addition, reported sleep latency increased by almost 1 h at high altitude [42].
The incidence of AMS has been studied at moderate altitude (2,000 m). Montgomery
et al. [43] found that AMS occurred in 25% of subjects at 2,000 m compared to 5%
at sea level.
Jafarian et al. evaluated high-altitude sleep (HAS) disturbance through the
Groningen Sleep Quality Scale (GSQS) after the first night’s stay at 3,500 m of
altitude for 100 participants. Sixty percent of participants reported sleep disturbance
(the most prevalent symptom), followed by headache in 49% [44].
Sleep studies have been performed at altitude to assess changes in sleep stages.
Miller et al. studied the effects of hypobaric hypoxia equivalent to an altitude of
4,268 m in four male and four female subjects. He observed increase in light sleep
(stage 1), with a decrease in stage 2 sleep and mild drop of stages 3 and 4. TST was
unchanged with no significant changes in REM sleep [45]. Johnson et al. evaluated
sleep architecture and its relationship to periodic breathing during incremental
increases in altitude in 19 normal subjects. Overnight polysomnography was
performed in 14 subjects at altitudes 0, 1,400, 3,500, 3,900, 4,200, and 5,000 m
above sea level. Time spent in stage 1 increased and time spent in SWS decreased
as altitude increased. Time spent in REM sleep was preserved. Sixteen subjects
developed periodic breathing during sleep at one or more altitudes. The occurrence
of periodic breathing increased with altitude from an average AHI of 20 events/h at
3,500 m up to 68 events/h at 5,000 m. Multiple arousals were seen as well (AI of 19
events/h at sea level vs. 29 events/h at 5,000 m). Subjects with periodic breathing
have more arousals, however, the number of arousals that occurred in association
with periodic breathing was typically only half the rate of the AHI. A good proportion
258 L. Bazan et al.

of the periodic breathing central apneas resolved in the absence of arousal. The
spontaneous arousals were not affected by the increase in altitude [46]. The poor
subjective quality of sleep may be attributed to either the multiple arousals asso-
ciated with the termination of apneas and onset of hypercapnea or to changes in
sleep stage distribution (e.g., increase stage 1 sleep) [47].
Following acute ascent to high altitude, sleep quality tends to improve with accli-
matization. Undertaking a slow ascent and slow rise should be seen as the best
measure to improve sleep at high altitude. However, some medications are available
for the treatment of this condition.

Carbonic Anhydrase Inhibitors: Acetazolamide

Administration of acetazolamide, a carbonic anhydrase inhibitor, is effective for

treating AMS given both prophylactically and symptomatically. Acetazolamide
inhibits carbonic anhydrase in the kidneys and lungs, promoting a slight metabolic
acidosis. This effect counters the hypocapnic alkalosis produced by hyperventilation.
As a result, AMS symptoms, including sleep disturbance, are reduced and the
acclimatization process is hastened [48]. Nicholson et al. administered 500 mg daily
of acetazolamide vs. placebo to six climbers during an expedition to the Himalayas.
Acetazolamide increased stage 2 sleep and reduced wakefulness [49]. Fischer et al.
found a slight decrease of stage 1 sleep, and increases in stage 4 and REM sleep on
the first night at high altitude after administration of acetazolamide 250 mg twice
daily for a couple of nights vs. placebo. Acetazolamide also improved oxygenation,
decreased AHI and desaturation index [50]. These studies did not measure subjective
sleep quality after acetazolamide. Other studies have demonstrated improvement
on AMS scores (calculated through a point system of symptoms which included
headache, loss of appetite, feeling sick, severe inappropriate weakness, dizziness,
depression, irritability, drowsiness, cough, and shortness of breath); insomnia was
not included as one of the symptoms after using acetazolamide [51]. The maximum
dose is 5 mg/kg/day, taken in two or three doses. However 125 mg a day, taken 2 or
3 times or once at bedtime, may be adequate [48].

Benzodiazepines

Temazepam has been studied as a treatment for insomnia at high altitude. Nicholson
studied the sleep and respiration of six climbers during an expedition to the
Himalayas. The subjects were assigned to age-matched pairs and were randomly
allocated acetazolamide (500 mg daily) or placebo, and for two nights during the
stay at high altitude (over 4,000 m) sleep was recorded one night with temazepam
10 mg and one night with matching placebo. Sleep was markedly disturbed in all
subjects above 4,000 m. Temazepam shortened the mean sleep onset latency of the
whole group from 33.8 to 22 min and increased the amount of REM sleep from 41.4
to 64.2 min. In the subjects not taking acetazolamide, temazepam increased stage 2
14 Management of Insomnia 259

from 125.3 to 167.3 min and in the subjects taking acetazolamide, temazepam in
combination shortened sleep onset latency from 41.1 to 17 min and increased sleep
efficiency from 73 to 88%. The subjects reported that they slept better at high altitude
with temazepam than with placebo. For the group, the number of respiratory distur-
bances was greater at high altitude than at sea level, but it was not possible to
establish any differences between those using acetazolamide or placebo, or between
those using the placebo and temazepam at high altitude [49]. Thus, hypnotics may
improve sleep at high altitude, even without affecting respiratory variables.
Nickol et al. [52] examined the efficacy and safety of temazepam on nocturnal
oxygenation and next-day performance at high altitude. Thirty-three subjects took
10 mg of temazepam and placebo in random order on two successive nights soon
after arrival at 5,000 m. Compared with placebo, temazepam resulted in a reduction
in periodic breathing, at the expense of a small but significant decrease in mean
nocturnal oxygen saturation from 78 to 76%. There was no change in sleep latency
or restlessness measured by actigraphy. Temazepam had no adverse effect on
next-day reaction time, maintenance of wakefulness, cognition or AMS scores.
Following temazepam compared with placebo, more subjects reported dropping off
to sleep quicker than usual and sleeping better although these differences did not
reach statistical significance.
It should be noted that doses as high as 30 mg of temazepam may be used for
sleep at sea level and the above-mentioned studies were done with only a 10 mg
dose. So, higher doses at high altitude have not been evaluated and cannot be recom-
mended, due to its potential for reduced oxygen saturation [53]. Also, the drop in
the oxygen saturation post-temazepam in healthy volunteers can be amplified in
patients with underlying lung disease. Since no studies have been done in patients
with pulmonary disease, this medication cannot be recommended in this population
either. However, it is useful to have an alternative to the use of acetazolamide in
patients with poor tolerance or with allergy to sulfa. Also it is important to know
that cognitive function was not worsened with the dose mentioned above.

Non-benzodiazepine Benzodiazepine Receptor Agonists

Studies evaluating the effect of these agents on symptoms of insomnia at high altitude
have been done either in a simulator or in the field. Chamber and field studies done
with zolpidem 10 mg and zaleplon 10 mg have demonstrated improvements in sleep
onset latency and latency to S2 and SWS with both drugs; however the effects on
SWS and TST were more significant with zolpidem. Neither zolpidem nor zaleplon
influenced respiratory parameters at altitude. Compared to placebo, the AHI index
or the mean or lowest SaO2 were not significantly affected by either drug. Cognitive
performance and attention capacity were not reduced, and physical performance
was not impaired, compared with a control night at sea level. AMS was also found
to be reduced under both medications [54–56]. Reports of amnesia and somnam-
bulism with the use of zolpidem, however, make this medication of potential risk
especially in climbers in unsecured areas [57–60].
260 L. Bazan et al.

Oral Steroids

Studies have shown amelioration of AMS symptoms with the use of dexametha-
sone. Dexamethasone 4 mg every 8 h starting 24 h before ascent or every 6 hours for
six doses were utilized in two different studies. Also the use of prednisolone has
been evaluated at high altitude. AMS symptoms were significantly lower compared
to either acetazolamide or placebo. In two studies the assessment of AMS symp-
toms included reports about feeling refreshed/unrefreshed or insomnia. A predniso-
lone dose of 20 mg once a day was considered optimal [61, 62].
It is still unknown which mechanisms allow dexamethasone or prednisolone
or other oral steroids, to improve AMS symptoms. It is postulated that steroids
may act to improve the integrity of capillary membranes and induce cerebral
vasoconstriction as it does with other types of vasogenic edema. Others postulate
that the beneficial effects in AMS primarily are achieved by enhancing mood and
relieving nausea [63]. More studies are required to determine the actual sleep pat-
tern in high altitude while on treatment with oral steroids as well as in the quality of
sleep and specifically in the improvement of insomnia.

Other Medication Used to Treat Insomnia at High Altitude

Phenytoin has been studied in the potential treatment of AMS symptoms; however, it
was found not to be effective [64]. Almitrine, a respiratory stimulant, was compared to
acetazolamide and placebo in four healthy subjects at 4,400 m. Almitrine and acetazol-
amide both increased oxygen saturation during sleep; however, almitrine increased peri-
odic breathing and acetazolamide was a superior agent at ameliorating periodic breathing
[65]. Since periodic breathing is associated with arousals during sleep at high altitude,
almitrine would not be an appropriate alternative to this type of insomnia. Theophylline
is a respiratory stimulant through a central effect in ventilation. In a study by Kupper
et al. [66], 20 healthy male volunteers were randomized to receive either 300 mg theo-
phylline daily or placebo during ascent, and during a stay at 4,559 m altitude as well as
5 days prior to the expedition. Seventeen subjects completed the study. Theophylline,
significantly reduced AMS symptoms, events of periodic breathing, and oxygen desatu-
rations. No significant differences in sleep efficiency or sleep structure were present in
the two groups. No adverse events associated to the drug were reported. Theophylline is
well known for its narrow therapeutic window and multiple drug interactions. Due to the
lack of clinical experience in AMS so far, it is not prudent to recommend this medication
until further evaluations are done, especially with regard to safety. No studies have been
done on the use of antihistamines for insomnia related to high altitude.

Medications Used to Treat Insomnia

In a National Sleep Foundation Poll, 28% of self-defined insomniacs had used

alcohol to help them fall asleep [67] and 23% used over-the-counter (OTC) medications
for the same. Forty percent indicated using one or the other [5]. Drugs such as
14 Management of Insomnia 261

Table 14.1 Food and Drug Administration (FDA)-approved hypnotics

Half-life
Type of drug Dose (mg) (hours) Insomnia indications
Benzodiazepinesa
Triazolam (Halcion) 0.125, 0.25 2–6
Temazepam (Restoril) 7.5, 15, 22.5, 30 8–20
Estazolam (ProSom) 1, 2 10–24
Flurazepam (Dalmane) 15, 30 48–120
Quazepam (Doral) 7.5, 15 39–73
Other benzodiazepine receptor agonists (BZRAs)
Zaleplon (Sonata) 5, 10, 20 1 Sleep-onset insomnia
Zolpidem (Ambien) 5, 10 1.5–2.4 Sleep-onset insomnia
Zolpidem CR (Ambien CR) 6.25, 12.5 1.6–4.5 Sleep-onset and maintenance
insomnia
Eszopiclone (Lunesta) 1, 2, 3 6 Sleep-onset and maintenance
insomnia
Melatonin receptor agonist
Ramelteon (Rozerem) 8 0.8–2 Sleep-onset insomnia
Tricyclic antidepressant/histamine-1 antagonist
Doxepin (Silenor) 3, 6 10–50 Sleep-maintenance insomnia
a
At the time these drugs were approved, there was no specific indication for onset or maintenance

alcohol, anesthetics, and narcotics can impair respiration due to the reduction of
both hypoxic and hypercapnic ventilatory responses and their suppressive effect on
maintenance of upper airway tone [16, 68].

Efficacy of Hypnotics

The most commonly used and most investigated medications used for the treatment
of insomnia are the benzodiazepine receptor agonists (BZRAs). These drugs func-
tion by binding to the benzodiazepine receptor at the GABA-A complex.
These receptors are present in the membranes of neurons in the central nervous
system (CNS) and peripheral nervous system (PNS). BZRAs include the tradi-
tional benzodiazepines, and a newer group of drugs called the non-benzodiazepines
(i.e., zaleplon, zolpiden, zolpidem CR, zopiclone, and eszopiclone) [69].
The efficacy of Food and Drug Administration (FDA)-approved hypnotics is
well documented. The medications listed in Table 14.1 have demonstrated efficacy
for time to sleep onset, and depending on duration of action (i.e., dose and half life)
reducing the duration of wake after sleep onset (WASO). All drugs have demon-
strated efficacy using both PSG end points as well as patient-reported outcomes.
Patient-reported outcomes are important as insomnia is a symptom-based diagnosis.
Most clinical trials on insomnia have been done in primary insomnia, where no
other disease states are present. This is important because it ensures that evaluations
of hypnotic efficacy are not confounded by aspects of comorbid disease states or
medications used to treat those diseases. However, as insomnia rarely presents as
262 L. Bazan et al.

primary, it is also critical to review the efficacy, benefits, and limitations (e.g., tolerance,
abuse potential) of therapeutic agents for insomnia in the context of common comor-
bities, particularly those that are encountered in pulmonary settings.
The most common insomnia comorbidity is depression. In a study of insomnia
comorbid with depression, eszoplicone significantly reduced the time to sleep onset
and reduced the amount of WASO [70]. More importantly it augmented the antide-
pressant response of fluoxetine. There are similar data with generalized anxiety
disorder, rheumatoid arthritis, as well as menopause [71–73]. Unfortunately, to date,
there are few studies with the aim of evaluating the efficacy of hypnotics in patients
with insomnia comorbid with pulmonary disorders. To the extent these have been
done, they have been done as safety studies. That is, they were performed and powered
to determine if hypnotics worsen respiration during sleep.
COPD affects approximately 14 million people in the United States and is the
fourth leading cause of mortality [74]. As mentioned previously, patients with COPD
have difficulties with sleep, with slightly more than 50% of those patients complain-
ing of difficulties initiating or maintaining sleep and 25% of them complaining of
daytime sleepiness [26]. A multicenter study confirmed that 44% of elderly Italians
with COPD had nocturnal awakenings, followed by morning tiredness (33%), early
morning awakenings (30%), and difficulty falling asleep (26%) [75].
Benzodiazepines have been studied in patients with COPD. Cohn et al. [76]
evaluated the effect of estazolam 2 mg vs. flurazepam 30 mg vs. placebo on the
cardiopulmonary function of 29 patients with mild to moderate COPD. Criteria for
entry included FEV1 ranged from 50 to 75%, end expiratory CO2 was £45 mmHg,
and oxygen saturation on room air ³85%. Although no difference on the ventilatory
responses to CO2 were found, flurazepam decreased oxygen saturation and inspira-
tory time and increased respiratory frequency. In another study, Beaupre et al. evalu-
ated the effect of therapeutically equivalent doses of diazepam (10 mg) and zopiclone
(7.5 mg) compared to placebo on the respiratory center output of moderate to severe
COPD patients (average FEV1 1 L). Diazepam produced a significant drop in the
output of the respiratory centers compared to placebo following CO2 rebreathing.
Zopiclone did not have any effect but produced an increase in respiratory frequency.
There was no difference between the two active treatments [77]. Another study
evaluated the effect of sublingual lorazepam 1.5–2 mg on the respiratory muscles of
patients with severe COPD (FEV1 0.91 L). That study showed a drop in ventilation,
reduction of the respiratory muscle strength, and resistance in patients with stable
severe COPD [78]. These studies suggest the need for caution with these agents due
to the potential for depression of the central respiratory drive in patients with COPD
and worsening hypoxemia with these agents. To our knowledge, no efficacy studies
with these agents in patients with COPD have been published.
Studies with short-acting non-benzodiazepine BZRAs such as zolpidem and
zaleplon, have shown no significant effects on respiration in patients with mild to
moderate COPD. In a study comparing zaleplon 10 mg, zolpidem 10 mg, and
placebo, there was no effect on the mean overnight SaO2 or the percentage of the
night with saturation less than 90% [79]. Girault et al. assessed the effects of repeated
10 mg oral doses of zolpidem compared to placebo on diurnal and nocturnal respira-
14 Management of Insomnia 263

tory function, as well as on diurnal vigilance and physical performance in ten COPD
patients with disordered sleep. Average FEV1 was 0.84 L. No impairment in nocturnal
respiratory and sleep architecture parameters were noticed, nor on diurnal pulmo-
nary function tests, central control of breathing, and physical evaluation [80].
The majority of studies so far have been done in patients with mild to moderate
COPD. Until more data are available on the safety and efficacy of other BZRAs in
patients with severe COPD, these agents cannot routinely be recommended.
However, in patients with mild to moderate COPD with no awake hypercapnea,
these agents can be useful [79].
Studies with Ramelteon, a melatonin receptor agonist, have been done in patients
with mild, moderate, and severe COPD and it has been found to significantly
increase TST and sleep efficiency without affecting oxyhemoglobin saturation,
which can be explained through its completely different mechanism of action com-
pared to the BZRAs [81–83]. Please refer to the section “Efficacy of Hypnotics” for
more extensive information on this hypnotic agent. To the knowledge of the author,
no studies on the use of doxepin in COPD patients have been published.
A prevalence of comorbid insomnia of 39–55% have been reported in patients
with OSA [84]. A retrospective study of 231 patients with sleep disordered breath-
ing (SDB) or upper airway resistance syndrome (UARS) showed a prevalence of
insomnia symptoms slightly over 50% (116/231). The group was divided into two
groups, the SDB plus insomnia (SDB+) and the SDB without insomnia symptoms
(SDB−). After comparing the two groups there was a significant difference in the
frequency of insomnia-related complaints such as sleep onset latency longer than
30 min (51% in SDB+ vs. 3% in SDB−), and difficulty returning to sleep once
awake (59% in SDB+ vs. 10% in SDB−). It was also found that compared with
patients with OSA alone, patients with both insomnia and OSA showed signifi-
cantly longer SOL (17 vs. 65 min), shorter TST (5.6 vs. 7.2 h), and lower sleep
efficiency (75% vs. 92%) by PSG [85]. In a prospective study of 105 patients
referred for evaluation of suspected OSA, 102 of those patients were diagnosed with
OSA and 39% of them met study criteria for insomnia. OSA severity was correlated
with insomnia-symptom severity score [86].
Pre-existing insomnia could be one of the factors that can affect compliance with
nasal CPAP; due to the sleep difficulties the CPAP mask can induce, including
frequent awakenings and inability to initiate or return to sleep with the mask in
place. In a retrospective chart review of 232 OSA patients treated with CPAP, 37%
of them reported at least one frequent insomnia complaint with 23.7% reporting
difficulty maintaining sleep, 20.6% reporting early morning awakening and 16.6%
reporting difficulty initiating sleep. Sleep maintenance insomnia showed a statisti-
cally significant negative relationship with average nightly minutes of CPAP use as
well as adherence status [87]. Since one of the predictors of chronic use of CPAP is
early adherence to CPAP [88], it is possible that early diagnosis of insomnia and its
treatment could help compliance with CPAP.
Insomnia coexists with anxiety and depression, and both pathologies may influ-
ence CPAP compliance. Patients with anxiety may be affected by claustrophobia,
which has been associated with poor CPAP compliance as well [89]. Benzodiazepines
264 L. Bazan et al.

are commonly used for the treatment of insomnia; however, a high level of caution
is recommended when these medications are considered in patients with OSA.
Studies using benzodiazepines have shown their detrimental effect on ventilatory
control, respiratory muscle function, and apnea events. A study comparing 30 mg of
flurazepam vs. placebo showed an increased of apnea episodes (9.95 vs. 5.35) and
longer duration of apneas (3.44 vs. 1.72 min) in the flurazepam group [90]. In another
study using triazolam 0.25 mg, patients with severe OSA showed an increased
arousal threshold which resulted in prolongation of event duration and increased
desaturation [91]. However, in another study using Temazepam 15–30 mg in elderly
subjects with mild sleep apnea and insomnia, there was no increase in the respiratory
disturbance index (RDI) as compared with the non-drug group [92]. The effect
could have been different if patients with moderate or severe OSA were included.
At this point, the regular use of benzodiazepines for insomnia in OSA patients
cannot be broadly recommended since it can produce worsening of the severity of
the underlying disease as well as hypoxemic events.
Non-benzodiazepine BZRAs have been studied in OSA patients as well. In a study
of 16 patients with severe OSA treated with CPAP, the use of zolpidem 10 mg did not
affect the AHI, oxygen desaturation index or the lowest oxygen saturation [93]. In
another study, zolpidem 10 mg was administered to ten healthy non-obese snorers.
Zolpidem increased TST, sleep efficiency, and the percentage of stage 2 sleep.
Zolpidem did not affect the TST spent snoring nor desaturation parameters. The RDI
was modestly increased by zolpidem from an average of 1.5–3 events/h, however this
is still under 5 which is within normal limits [94]. A pilot study on patients with mild
to moderate OSA (AHI ³10 and £40) received eszopiclone 3 mg vs. placebo. The
night of the study, patients were not allowed to use CPAP. There was no worsening on
the AHI while on eszopiclone, and there was improvement in sleep maintenance and
sleep efficiency [95]. The use of eszopiclone 3 mg has also been shown to improve the
quality of diagnostic PSG and CPAP titration. Eszopiclone reduced sleep latency,
improved sleep efficiency, reduced WASO, and prolonged sleep time [96]. It has also
been demonstrated that the use of 3 mg of eszopiclone for 14 days at the onset of
CPAP therapy improves long-term CPAP adherence compared to placebo in adults
with OSA. The eszopiclone group used CPAP for 21% more nights, 1.3 more hours
per night for all nights, and 1.1 more hours per nights when CPAP was used. The
hazard ratio for discontinuation of CPAP was 1.9 times higher in the placebo group
[96]. The effect of these hypnotics in patients with severe sleep apnea determined by
either AHI or associated severe desaturation, has yet to be determined. However, the
use of these hypnotics in association with CPAP looks to be safe and may improve
adherence to CPAP therapy. We do not yet know what specific group of patients will
benefit the most from this combination. Thus far, the use of zolpidem or eszopiclone
in patients with OSA with or without insomnia, have improved CPAP compliance.
However, to our knowledge, studies to assess CPAP compliance improvement on
patients with insomnia and OSA have not been published.
In a recent study, ramelteon, a melatonin receptor agonist, was used in older
adults with insomnia and sleep apnea who started treatment with auto-titrating
positive airway pressure (APAP) therapy for sleep apnea. Ramelteon 8 mg for 4
14 Management of Insomnia 265

weeks was compared to placebo. Ramelteon was effective at improving objective

but not subjective sleep onset latency in this group of patients and it did not improve
APAP adherence [97]. Further research is required with this medication especially
in patients with sleep onset insomnia prior to further recommendations. Thus far,
due to the mechanism of action of Ramalteon and through efficacy and safety stud-
ies done in patients with mild to severe COPD, it has been shown not to affect AHI
or to worsen hypoxemia [81–83].

Safety of Medications Commonly Used in Insomnia

When traditional benzodiazepines were introduced approximately five decades ago

as a treatment for insomnia, they represented a major advance in the therapy of this
disorder. They are more effective and safer than drugs used previously, such as bar-
biturates. However, concern about side effects, tolerance, and dependence has been
raised [98]. The major adverse effects of BZRAs include psychomotor and cognitive
(anterograde amnesia) impairment, discontinuation effects (i.e., rebound insomnia),
and risk of dependence. The incidence and severity of these side effects, particularly
residual impairment upon awakening, are primarily determined by drug dosage and
half-life which determine the duration of action of medications. Thus, the longer the
half-life or the higher the dose, the greater the likelihood of residual effects. In terms
of the amnesic effects, all BZRAs produce anterograde amnesia and this seems to be
related to both binding specificity and sedative potency.
Tolerance to a drug is defined as the reduction of its effect with repeated adminis-
tration of a constant dose, or the need to increase the dose to sustain a specific level
of effect. Tolerance to the hypnotic effects of BZRAs does not develop in the vast
majority of studies, at least for therapeutic doses and for the periods of time (3–6
months) that have been studied [99]. These consistent clinical trial findings are incon-
sistent with many clinicians view that tolerance to these medications does occur with
chronic use. This causes clinicians to use the lowest possible dose. Thus, the loss of
efficacy may really be a worsening of the insomnia or the comorbid disorder.
Dependence has been a concern with hypnotic medications. Epidemiologic
data has shown that for 74% of users of hypnotics the longest period of daily use
was less than 2 weeks [100]. 1% of individuals use them nightly on a chronic basis
with rare dose escalation. It is unlikely that this pattern of use reflects dependence
in the vast majority of patients, given the absence of dose escalation or non-thera-
peutic use of the medication [101–103]. Although there are reports of physical
dependence at therapeutic doses in long-term daytime use of benzodiazepines for
treating anxiety disorders, no such data has been found in insomnia patients.
Daytime studies of the reinforcing effects of these drugs indicate that they have a
low behavioral dependence liability [104].
However, it is important to recognize that individuals with a risk for abuse, will
abuse BZRAs. Abuse of sedatives, particularly the benzodiazepines diazepam (anxi-
olytic) and flunitrazepam (hypnotic not approved in US), has been a particular problem
266 L. Bazan et al.

in populations of abuse such as methadone maintenance patients and intravenous drug

abusers. On a population basis, the incidence of recreational abuse of sedatives/
hypnotics and related drugs is relatively rare, but it is similar to the incidence of abuse
of other illicit substances. The risk of abuse or problematic use of hypnotic drugs is
significantly elevated among patients with histories of drug or alcohol abuse or
dependence [105]. Based on this information, physicians are strongly discouraged
from prescribing BZRA hypnotics to patients with a history of drug abuse.
More recently, the non-benzodiazepine BZRAs were developed and act
predominantly at the a 1 subunit through the a 3 subunits. Studies with genetically
modified mice have confirmed that receptors containing a 1 subunits play a particu-
larly important role in mediating sedative activity as well as the amnestic effects of
these compounds. It has been hypothesized that non-benzodiazepine BZRAs pro-
duce fewer adverse side effects on pulmonary function than do the benzodiazepines
[106]. Drugs in this subclass include zolpidem, zolpidem CR, zopiclone, and its
active racemate eszopiclone and zaleplon as listed in Table 14.1. While zolpidem
and zaleplon are highly selective for the a 1 subunit, zopiclone and eszopiclone are
less selective with comparable affinity for a 1, a 2, a 3, and a 5 subunits [69, 107].
The non-benzodiazepine BZRAs have similar effects on sleep latency and main-
tenance as traditional benzodiazepines [69]. Differences in the relative efficacy for
the BZRAs relate most importantly to dose and half-life, the primary determinants
of duration of action. Overall, shorter acting hypnotics such as zaleplon (t1/2 = 1 h)
and zolpidem (t1/2 = 2–6 h) are effective at improving sleep onset latency while
higher doses or longer-acting compounds are also effective for maintaining sleep.
Several studies have been performed to test the safety of these medications on
pulmonary and cognitive function. Ranlov and Nielsen compared the effects of equi-
potent, single intravenous doses of zopiclone (7.5 mg) and diazepam (10 mg) on
ventilatory responses in ten healthy volunteers. Ventilatory parameters were mea-
sured before and after the injections during the early afternoon in the wake state. The
intravenous administration of diazepam induced a significant reduction in the CO2
stimulated ventilatory responses. The total ventilation after 5 and 35 min of the zopiclone
injection during the 4 min of CO2 rebreathing experiment was 3.35 and 3.01 L/m2/
PCO2, respectively. The total ventilation of 5 and 35 min injection of diazepam was
2.83 and 2.55 L/m2/PCO2 which was significantly lower. While on zopiclone and
after the rebreathing method, the respiratory rate also increases from a baseline of
16.7 bpm to a range between 19.5 and 20.4 bpm over a period of 4 min during the
rebreathing method. This effect was not seen after the injection of diazepam [108].
Cohn evaluated the effects of single oral doses of zolpidem 10 or 20 mg, codeine
phosphate 60 mg, or placebo in wake normal volunteers. Ventilatory responses to CO2
and mouth occlusion pressure, measured 1 hour before and at 1 and 3 hours after
each administered dose (approximate t-max), were not significantly affected by
either zolpidem each administered dose; however, codeine phosphate produced a small
but significant respiratory suppressant effect at 3 hours. Non-significant changes in
mean inspiratory flow were noted after zolpidem 10 mg. Two hours after administra-
tion of zolpidem 20 mg, mean inspiratory flow was significantly lower than after pla-
cebo, possibly related to some individuals falling asleep during data collection [109].
14 Management of Insomnia 267

Berry et al. evaluated the effect of triazolam on the arousal response to airway
occlusion during NREM sleep. Mask occlusion was performed 1–4 h after triazo-
lam 25 mg or placebo ingestion, while the subjects breathed a mixture of air and
oxygen adjusted to produce an arterial oxygen saturation of 98%. Time to arousal
was significantly longer on triazolam nights (32 ± 5.2 vs. 22.5 ± 3.2 s). The maximal
airway suction pressure preceding arousal was also significantly higher on triazolam
nights (26.5 ± 2 vs. 20 ± 1.2 cm H2O). Conversely, the rate of increase in inspiratory
effort (maximal pressure) during occlusion was not decreased by triazolam [110].
This arousal blunting effect of hypnotics is important to consider in patients with
OSA where the termination of the obstructive event depends largely on arousal.
More broadly, most physiological responses produced by internal stimuli (e.g. cough)
require arousal, and blunting the arousal response may have negative consequences.
However, blunting arousal response may help sleep by preventing arousal to exter-
nal stimuli. In patients with comorbid medical conditions potential negative conse-
quences need to be considered. In addition, there are the potential amnestic and
cognitive effects that non-benzodiazepines BZRAs have, similar to benzodiazepines
[111]. There are also reports of abnormal behaviors in sleep such as sleep eating,
sleep walking, and anterograde amnesia associated with zolpidem use [112].
Ramelteon, a melatonin receptor agonist, is a hypnotic agent approved by the US
FDA in 2005 for the treatment of insomnia characterized by difficulty falling asleep and
it is not a controlled substance [113]. Three melatonin receptors, MT1, MT2, and MT3,
have been identified with wide distribution throughout the body and brain. The sleep-
promoting effect of ramelteon is mediated by MT1/MT2 receptors. Ramelteon has no
affinity for the MT3 receptor which may mediate other functions including effects on
the gastrointestinal system [69]. Ramelteon has no known affinity for the benzodiaz-
epine or any other receptor at the GABA-A complex or receptors that bind neuropep-
tides, cytokines, serotonin, dopamine, noradrenaline, or opiates [113]. In clinical
trials, ramelteon has produced significant reductions in latency to persistent sleep com-
pared with placebo. Additionally, improvements in TST were sometimes observed.
The most common adverse events reported with ramelteon included headache (7%),
dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%) [113].
Some physicians who prescribe sedative hypnotics are concerned about the pos-
sibility of dependence especially in patients with prior history of abuse. Johnson
et al. evaluated the abuse potential of ramelteon in doses up to 160 mg. Compared
with placebo and triazolam, ramelteon showed no significant effect on measures
related to abuse [114].
No studies have been done so far to assess the effect of ramelteon on control of
breathing. However, studies that assess the effect of ramelteon on respiration have
been done in patients with mild to moderate COPD, moderate to severe COPD, and
mild to moderate OSA. In those studies, there was no significant difference in the
level of oxyhemoglobin saturation throughout the night and no increase in the AHI
between the ramelteon and the placebo nights. In patients with moderate to severe
COPD, ramelteon has been found to significantly increase TST and sleep efficiency
[81–83]. These findings have expanded our options for treatment of insomnia in
patients with prior history of substance abuse and lung disease.
268 L. Bazan et al.

Sedating Antidepressants

As the highest comorbidity with insomnia is depression, it is not surprising that

the most common medications utilized in the United States for off label treatment
of insomnia are the sedating antidepressants. Leger and Poursain [115] found that
when patients in United States were prescribed a medication for insomnia, 22% of
the time they were prescribed sedating antidepressants. In 2002, trazodone was the
most prescribed drug for insomnia, with amitriptyline and mirtazapine ranked as
third and fourth, respectively [104]. However, there is little evidence to support
their use as a treatment for insomnia without depression [116]. Importantly, while
we know the range of doses that are effective in depression, and the side effects
associated with those doses, no one knows the doses that are effective for insomnia
and the side effects of those doses. Several antidepressants are commonly used for
the treatment of insomnia, even in patients without concomitant anxiety/depressive
disorders and despite the lack of evidence regarding their efficacy or safety. Among
the antidepressants those which are histamine antagonists, and 5HT2A or 5HT2C
antagonists are the ones most commonly used.
Doxepin was approved in 2010 by the FDA for the treatment of insomnia char-
acterized by difficulty in maintaining sleep. Doxepin is a tricyclic antidepressant
(TCA) with relatively selective antagonism of the histamine 1 (H1) receptor at the
doses approved for insomnia (i.e., 3 and 6 mg). H1 antihistamines have sedative
properties. At antidepressant doses (75 mg and higher), Doxepin inhibits postsyn-
aptic H2, serotonin 5HT2, adrenergic a 1, and muscarinic receptors, but has little
effect on postsynaptic dopaminergic D2 and adrenergic a 2 receptors [117].
However, as the dose of doxepin lowers, it is a highly selective H1-receptor antago-
nist, four times more potent than amitryptiline and 800 times more potent than
diphenydramine [118]. Doxepin has been studied at doses of 1, 3, and 6 mg in
young and elderly patients with transient and chronic insomnia [119–122]. In those
studies, doxepin showed significant improvement in WASO, TST, and overall sleep
efficiency (SE), even at the 1 mg dose. With higher doses, sleep efficiency showed
further improvement. Significant improvement in sleep efficiency at all doses in the
final third of the night was also demonstrated which emphasizes its therapeutic
potential in patients with sleep maintenance insomnia, a common complaint in
patients with underlying obstructive lung disease [26]. Also, due to its mechanism
of action, it is unlikely that it will affect pulmonary function or ventilator parameters
during sleep; however, those studies have yet to be done. At all three doses doxepin
did not show statistical differences in next-day residual sedation and sleep architec-
ture was preserved relative to placebo. The most common treatment emergent
adverse events that occurred with doxepin relative to placebo were somnolence/
sedation, upper respiratory tract infection/nasopharyngitis, gastrointestinal effects
(gastroenteritis, nausea), and hypertension [117]. There was no evidence of physical
dependence or worsening insomnia after doxepin discontinuation.
Trazodone has been utilized frequently for the treatment of insomnia, even though
it is not an FDA-approved hypnotic. Trazodone is a phenylpiperazine-sedating
14 Management of Insomnia 269

antidepressant. It is a weak but specific inhibitor of the serotonin reuptake transporter

with minimal affinity for NE or dopamine reuptake. Trazodone also inhibits different
serotonin receptors. The sedating mechanism is not well elucidated but it is pre-
sumed to be related to its antihistaminergic or antiserotoninergic activity similar to
other sedating antidepressants such as TCAs [116, 123]. As an antidepressant, tra-
zodone has the advantages of low cost, no restrictions on long-term prescription, and
low abuse potential. However, side effects of trazodone include orthostatic hypoten-
sion, blurred vision, nausea, dry mouth, constipation, drowsiness, headaches, and has
been associated with cardiac arrhythmias [116, 124]. The question remains at what
doses does trazodone improve insomnia, and are these side effects present at those
doses. There are virtually no studies to assess the effect of trazodone in respiratory
function or in patients with pulmonary disorders. Due to its mechanism of action,
problems with ventilation are not expected necessarily. However, that will need to be
assessed prior to recommending this medication based on the potential for significant
side effects. Given the common side effects of trazodone and the potential for toler-
ance to develop with just 2 weeks of treatment, it is unclear if the risk/benefit ratio
warrants trazodone’s use in non-depressed patients with insomnia [125].

Cognitive-Behavioral Therapy of Insomnia

Psychological and behavioral therapies for insomnia include sleep restriction,

stimulus-control therapy, relaxation training, cognitive strategies, sleep hygiene
education, and combined CBT. The main objective of CBT is to alter those factors
that perpetuate or exacerbate sleep disturbances such as poor sleep habits, irregular
sleep-wake schedules, hyperarousal, inadequate sleep hygiene, and misconceptions
about sleep and the consequences of insomnia. CBT is mainly indicated in patients
with persistent insomnia, either primary or comorbid. There are no actual contrain-
dications to CBT. However, one of its components, sleep restriction, can produce
sleepiness and patients should be cautioned about that possibility. Studies have
shown that CBT is effective for treating insomnia associated with chronic pain,
fibromyalgia, cancer, and various medical conditions in older adults [126]. CBT has
also been tested in patients with COPD and OSA with comorbid insomnia. After
CBT, these patients showed improvement in several self-reported measures of sleep
along with improvement on reports of daytime functioning [127, 128].

Other Medications

Other medications used in the treatment of insomnia including antipsychotics, que-

tiapine, and olanzapine have been used in the treatment of insomnia in patients with-
out psychiatric comorbidities. Their sleep effect is thought to be related to their
antihistaminc activity. There is no information on their efficacy and safety when used
as hypnotics in primary insomnia [98]. OTC sleep medications most commonly
270 L. Bazan et al.

contain dyphenhydramine (25 mg), a well-known H1 antihistamine as the active

ingredient. Their hypnotic effect is variable and can result in daytime sleepiness,
cognitive impairment, and anticholinergic effects that persist a day after ingestion,
potentially affecting driving performance [129]. Importantly, tolerance develops rap-
idly (~4–5 days) to the sedative effects of diphenhydramine [130]. BZD anxiolytics
have also been used for the treatment of insomnia. These include clonazepam, alpra-
zolam, and lorazepam. Their half-lives are longer than the hypnotics in the same
class. There are no studies done to assess safety or efficacy when BZD anxiolytics
are used as hypnotics [98]. Very few studies have been done to assess the efficacy and
safety of the use of herbal agents to treat insomnia. Some studies have been done
with valerian showing no improvement on self-reported or PSG sleep relative to
placebo. St John’s Wort is another herbal product promoted for the treatment of dif-
ferent conditions, such as depression, anxiety, and sleep disturbances. No studies
have been done to assess its efficacy or safety on the treatment of insomnia [131].

Summary of Keypoints

• The majority of people with insomnia have comorbid medical disorders, such as
conditions causing hypoxemia and dyspnea, gastroesophageal reflux disease,
pain conditions, and neurodegenerative diseases. Treatment can be challenging,
especially if multiple comorbidities are present.
• The curriculum of medical education lacks attention to sleep disorders and physi-
cians in general often fail to ask patients about their sleep.
• Treatment for insomnia includes CBT and pharmacological therapy.
• Patients with a variety of pulmonary disorders often suffer from sleep disturbance.
However, further differentiation between sleep initiation and sleep maintenance
insomnia is lacking. This differentiation should be made clear in order to effec-
tively guide pharmacological therapy.
• Studies to assess safety and efficacy of benzodiazepines and non-benzodiazepine
BZRAs have been conducted especially in patients with COPD but not in other
pulmonary disorders such as ILD and restrictive thoracic cage disorders (RTCD).
• Benzodiazepines have shown to produce a drop in ventilation, reduction of the
respiratory muscle strength, and increases upper airway resistance in patients
with stable severe COPD.
• Studies with short-acting non-benzodiazepine BZRAs such as zolpidem and
zaleplon, have shown no significant effects on respiration in patients with mild to
moderate COPD. Until more data are available in patients with severe COPD,
these agents cannot routinely be recommended. However, in patients with mild
to moderate COPD with no awake hypercapnea, these agents can be useful.
• Ramelteon, a new FDA-approved hypnotic for initiation insomnia has been
evaluated among patients with mild to severe COPD and has been found to be
safe and efficacious for the treatment of insomnia.
14 Management of Insomnia 271

• New FDA-approved hypnotics such as ramelteon and doxepin, due to their lack
of broad CNS suppression, might be safe in patients with respiratory disorders;
however, safety and efficacy studies are still needed.
• Patients with OSA show sleep onset and sleep maintenance insomnia. The use of
benzodiazepines increases the frequency of apneas and prolongs the duration of
apnea events. The use of non-benzodiazepine BZRAs have not worsened the
AHI or duration of apneas. Also some non-benzodiazepine BZRAs increase
compliance with CPAP. But this needs to be studied in patients with concomitant
insomnia and OSA.
• CBT has been tested in patients with COPD and OSA with comorbid insomnia.
After CBT, these patients showed improvement in several self-reported measures
of sleep along with improvement in daytime functioning. Further studies on the
safety and efficacy of CBT in patients with other pulmonary disorders and
comorbid insomnia are needed.

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Chapter 15
Circadian Disorders

Brandon S. Lu, Jeff Kwon, and Phyllis C. Zee

Keywords Circadian • Light • Melatonin • Sleep phase • Jet lag • Shift work

Circadian Biology

Circadian rhythms are near-24 h cycles that exist in all living organisms. Examples
in humans include the core body temperature rhythm, hormonal secretion rhythms,
and the sleep/wake cycle. Lung function and heart rate also demonstrate circadian
rhythmicity in that they cycle daily even in the absence of external influence [1, 2].
The master clock which regulates and coordinates the body’s many rhythms is the
suprachiasmatic nucleus (SCN) of the anterior hypothalamus [3]. The molecular
machinery in the SCN neurons that generates and perpetuates the circadian rhythm
consists of clock gene products which autoregulate their own expression through a
complex system of transcriptional, translational, and post-translational processes
[4]. These clock genes are also expressed in various other tissues in the body, e.g.,
heart [5], liver [6], lungs [7], and kidney [8], generating circadian rhythmicity to
numerous physiological parameters. In fact, about 10% of all genes in the heart and
liver have a circadian pattern of expression, underscoring the importance of circa-
dian regulation in normal physiology.

B.S. Lu
Department of Medicine, California Pacific Medical Center,
San Francisco, CA, USA
J. Kwon (*)
Division of Pulmonary, Critical Care, and Sleep Medicine,
Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA
e-mail: [email protected]
P.C. Zee
Department of Neurology, Sleep Disorders Center,
Northwestern University, Chicago, IL, USA

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 277
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_15,
© Springer Science+Business Media, LLC 2012
278 B.S. Lu et al.

Fig. 15.1 Phase-response

Advances
curve to light and melatonin.
Circadian time 0 = time of 2 Light

Phase Shift (hours)

temperature nadir. Note the
Melatonin
magnitude of phase shift to
light as compared to
melatonin. Adapted with 0
permission from Minors et al.
[34] and Burgess et al. [16]

Delays
-2

-12 -8 -4 0 4 8 12
Circadian Time

The most evident human circadian rhythm is the sleep/wake cycle. The prevailing
model of human sleep regulation describes the interaction between the circadian
system and the homeostatic sleep process such that the circadian clock promotes and
maintains wakefulness during the day while the homeostatic sleep process opposes
the circadian system by monotonically increasing sleep tendency throughout the
waking period until sleep is achieved in the evening [9, 10]. There is actually a bipha-
sic circadian rhythm to sleep tendency, with a dip in alertness approximately 6–8 h
after waking, followed by an increase in alertness through the early evening hours
[11]. Sleep homeostasis is gradually dissipated throughout the sleep period. The
sleep/wake cycle is thus the result of complex interaction between two systems.
While the sleep/wake cycle may be an outward display of the circadian rhythm,
classical phase markers of the endogenous circadian rhythm that are commonly used
in research include melatonin rhythm and body temperature rhythm. Both rhythms
have distinct phase relationships with the sleep/wake cycle such that the dim light
melatonin onset (DLMO – time at which melatonin level starts to rise) is about 2–2.5 h
before sleep onset and core body temperature nadir is about 2 h before sleep offset
[12] in normal phase individuals. As expected, when circadian rhythm is phase shifted,
the endogenous melatonin and body temperature rhythms will shift accordingly.
The free-running period (the frequency of oscillation) of the human endogenous
circadian clock is usually slightly longer than 24 h; therefore, the SCN must
synchronize or entrain itself to the 24 h environment daily in order for sleep/wake
to occur at the same time every day [13]. This entrainment is best accomplished by
light exposure, physical activity, and melatonin from the pineal gland. Light input
to the SCN, through the ganglion cells of the retina, is the most potent entraining
agent and the effect of light on the circadian system is dependent on the timing of
exposure. Light exposure during the first half of the night will delay the timing
of the circadian rhythm, whereas early morning light exposure will advance the
rhythm [14, 15]. Melatonin secretion from the pineal gland occurs during the night
15 Circadian Disorders 279

via input from the SCN and exogenous melatonin administration can also influence
the circadian system. Opposite to the effect of light exposure, melatonin given at
night will advance the timing of the circadian rhythm and early morning dosing will
delay the rhythm [16] (Fig. 15.1). Light and melatonin are often used in the
treatment of circadian rhythm sleep disorders (CRSD).

Circadian Rhythm Sleep Disorders

CRSD result from either alterations of the intrinsic circadian clock (delayed sleep
phase disorder (DSPD), advanced sleep phase disorder (ASPD), free-running type,
and irregular sleep–wake rhythm) or misalignment between the intrinsic circadian
rhythm and the external 24-h environment (shift work and jet lag) which leads to
symptoms of insomnia or excessive daytime sleepiness. In addition, The International
Classification of Sleep Disorders states that the sleep disturbance in a CRSD must
be associated with social, occupation, or other functional impairments [17]. Besides
physiological and environmental factors, maladaptive behaviors can influence the
clinical course of CRSD.

Delayed Sleep Phase Disorder

DSPD is characterized by chronic inability to fall asleep and wake up at desired

times. Typically the patient cannot fall asleep until 2–6 a.m., and when not con-
strained by social or work schedule, will wake up between 10 a.m. and 1 p.m. [18].
Because most patients attempt to conform to conventional work and school sched-
ules, however, they complain of insomnia and excessive daytime sleepiness. When
not required to maintain a strict schedule (i.e., on weekends and holidays), patients
report a normal sleep period without sleep complaints. DSPD is one of the more
common CRSD, affecting 0.17% of general population and greater than 7% of
adolescents [19, 20].
Although the exact pathophysiology is unknown, proposed mechanisms
include a prolonged circadian period, hypersensitivity to evening light which
delays the circadian clock, and altered homeostatic regulation of sleep to prevent
phase advancement [21, 22]. Genetic studies have suggested an autosomal domi-
nant mode of inheritance with incomplete penetrance, and genetic polymorphism
of several clock genes have shown associations with DSPD [23]. Per3,
Arylalkylamine N-acetyltransferase, and Clock have all been implicated, but
interestingly, both alleles of the Per3 length polymorphism have shown association
with DSPD [24–26]. Specifically, the four-repeat allele of the polymorphism, and
not the five-repeat allele, was associated with DSPD in a European cohort while
only the five-repeat allele of the polymorphism was associated with DSPD in a
South American cohort [24, 27].
280 B.S. Lu et al.

Diagnosis of Delayed Sleep Phase Disorder

Most of the patients who present with DSPD are adolescents or young adults,
although DSPD has also been described in older adults [28]. Diagnosis of DSPD
can usually be made from a detailed sleep history along with sleep diary and/or
actigraphy for at least 7 days in order to capture weekend or non-working days to
ensure patients exhibit a delayed sleep and wake pattern. Actigraphy utilizes a wrist-
worn motion detector to monitor sleep and wake pattern for long periods (usually
days to weeks). Polysomnography is not necessary for the diagnosis of DSPD unless
there is concern for concomitant sleep apnea or periodic limb movement disorders
[29]. When performed during the patient’s desired sleep and wake period, polysom-
nography should demonstrate normal sleep architecture and sleep stage distribution;
however, sleep onset latency may be prolonged [30].
Diagnosis of DSPD should only be made after exclusion of other causes of insom-
nia and daytime sleepiness. DSPD should also be differentiated from late sleep and
wake times which do not lead to daytime functional impairments. Both primary and
comorbid insomnias can have features of sleep-onset insomnia, but a patient with
DSPD will not have insomnia when allowed to sleep at desired time. Daytime sleepi-
ness may also be caused by other sleep disorders (e.g., sleep apnea, narcolepsy, etc.)
medical, neurological, and psychiatric disorders, as well as medication and substance
abuse. The circadian nature of DSPD should allow differentiation from other similar
complaints. DSPD is strongly associated with mood disorders, including depression
and anxiety, and psychiatric screening should be considered for patients [31, 32].

Treatment of Delayed Sleep Phase Disorder

Treatment of DSPD is aimed at realigning the endogenous circadian rhythm, and

hence the sleep/wake cycle, with the desired social and work schedule. Options for
advancing the timing of the sleep/wake cycle include chronotherapy, bright light
therapy, and melatonin administration. Chronotherapy is a method by which an
individual is phase delayed 3 h every 2 days until the desired sleep time is achieved
[33]. Although an effective therapy, chronotherapy is disruptive to the daily routine
and requires strict adherence to control of light exposure and sleep/wake times.
Chronotherapy was initially implemented on an in-patient basis, but has since been
successfully performed at home with well-structured, patient driven protocol. The
major limitations of chronotherapy are the duration of therapy and the restrictions it
places on social and professional responsibilities. While the therapy lacks any
controlled studies, it nevertheless is a viable treatment option for DSPD [29].
Bright light therapy is effective at altering the phase of the sleep/wake cycle [14].
The influence of light on the human circadian rhythm depends on the timing
and intensity of light exposure and is described by the phase-response curve of light
[14, 34]. Light given before the body’s temperature nadir will phase delay the circadian
rhythm, while light given after temperature nadir will cause a phase advance. In general,
light given closer to temperature nadir will cause a more dramatic phase shift.
15 Circadian Disorders 281

Table 15.1 Overview of diagnosis and treatment of circadian rhythm sleep disorders (CRSD)
Circadian disorder Main diagnostic criteria Treatment
Delayed sleep Delay in sleep period relative to Sleep hygiene
phase disorder desired sleep and wake times, Bright light therapy: 2,000–2,500 lx
causing insomnia and for 2–3 h prior to or at rise time
difficulty waking up Melatonin (1–3 mg): 5–7 h before
sleep time
Advanced sleep Advance in sleep period relative Bright light therapy: 2,000–2,500 lx
phase disorder to desired sleep and wake for 1–2 h in evening (approxi-
times, causing difficulty mately 7–9 p.m.)
staying awake in the evening Melatonin (theoretical benefit):
and inability to stay asleep in 1–3 mg after rise time
the morning
Shift work disorder Excessive sleepiness and Sleep hygiene
reduced performance during Bright light therapy: 2,500–9,500 lx
work shifts that overlap for 2 h during work shift
with the usual sleep period. Melatonin: 1–3 mg before sleep time
Insomnia symptoms and Caffeine
shortened or fragmented Scheduled naps: 1–2 h nap prior to
sleep, especially during work shift. Short 10–20 min naps
the day during work shift
Modafinil 200 mg or armodafinil
150 mg: take 1 h prior to work
shift
Jet lag Eastward travel: Difficulty Sleep hygiene
falling asleep in the evening. Eastward travel: avoid evening light
Excessive sleepiness and Bright light in the mornings
grogginess in the morning
Westward travel: Excessive Melatonin 1–5 mg at local bedtime
sleepiness in the afternoon Westward travel: avoid morning light
or early evening. Early Bright light in the evenings
morning or middle of the
night awakening

The American Academy of Sleep Medicine recommends morning light therapy for
the treatment of DSPD but the exact timing, duration, and intensity of light have not
been determined [29]. Based on two controlled trials, 2,000–2,500 lx of light for
2–3 h prior to or at rise time is recommended. Caution should be taken to not start
light therapy before temperature nadir to avoid further phase delay. Avoidance of
bright light in the evening is also advised.
The mainstay of pharmacotherapy for DSPD is melatonin. Similar to light therapy,
exogenous melatonin can shift the circadian rhythm based on the phase-response
curve of melatonin. Maximum phase advance is seen when melatonin is administered
3–5 h before DLMO in normal phase individuals [16, 35]. Studies using melatonin for
DSPD patients have used different doses and have shown different optimal times of
administration. One study found that 0.3 or 3 mg of melatonin caused the greatest
sleep phase advancement approximately 6 h before sleep onset in DSPD patients [36].
Hypnotics and stimulants have not been well studied for treating the symptoms of
DSPD and are currently not indicated for the disorder (Table 15.1) [29].
282 B.S. Lu et al.

Successful management of DSPD often requires a multimodal approach.

In addition to bright light and melatonin, patients should be instructed on proper
sleep hygiene. Discussion with the patient on treatment compliance is important
for difficult therapeutic options such as chronotherapy and bright light therapy. It is
also essential to identify and treat comorbid psychiatric disorders as well as minimize
maladaptive behaviors [37].

Advanced Sleep Phase Disorder

ASPD is characterized by sleep/wake times that are several hours earlier than
desired or conventional times. Affected individuals have habitual sleep time between
6 and 9 p.m., and wake time between 2 and 5 a.m., and staying up past 9 p.m. is
often very difficult. The prevalence of ASPD is much lower than that of DSPD,
estimated at approximately 1% of middle-aged adults [38]. Underreporting may
contribute to the lower prevalence of ASPD as an early sleep pattern tends to lead to
less work and social conflicts compared to a late sleep pattern. Although ASPD is
widely believed to be more common with aging, conclusive data are lacking to sup-
port this belief [39]. However, a survey of adults 40–65 years of age did find that
“advance-related” complaints were twice as common as “delay-related” complaints
(7.4% vs. 3.1%) [28].
Similar to DSPD, the etiology of ASPD is not well defined and could be multi-
factorial. Potential mechanisms include a shortened circadian period, as found in
one patient from a family of ASPD subjects, and retinal hypersensitivity to light in
the morning, which may maintain phase advancement of the circadian rhythm [40,
41]. Genetic analysis of ASPD families has revealed an autosomal dominant inheri-
tance pattern and a missense mutation of the clock gene Per2 [42, 43]. Highlighting
the genetic heterogeneity of the disorder, other families with ASPD did not have the
same mutation; instead, a mutation in the CKId gene was recently found in a sepa-
rate family with ASPD [44].

Diagnosis of Advanced Sleep Phase Disorder

Chronic complaints of early evening sleepiness and early morning awakening/insom-

nia are always present patients with ASPD. When trying to conform to a conven-
tional sleep schedule due to work or social obligations, patients become progressively
sleep deprived as bedtime becomes delayed and they continue to wake up earlier
than desired. As a result, patients often complain of excessive daytime sleepiness.
Sleep diary and/or wrist actigraphy recording for at least 7 consecutive days is
recommended to demonstrate stably advanced sleep and wake times, especially on
weekend or non-working days. Polysomnography performed at the patient’s desired
sleep time should show normal sleep architecture and total sleep time. It can also be
15 Circadian Disorders 283

useful to exclude other sleep disorders that can lead to daytime hypersomnia [17].
The prominence of early morning awakening as a symptom in ASPD should prompt
an evaluation for comorbid depression.

Treatment of Advanced Sleep Phase Disorder

Bright light therapy and chronotherapy have been used to delay sleep/wake times in
ASPD with success. Evening bright light has been shown to delay sleep onset and
morning awakening, increase total sleep time, and reduce wake after sleep onset. As
expected, body temperature and melatonin rhythms are also delayed with light [45,
46]. The duration and timing of light treatment and light intensity have not been
clearly defined [29].
Chronotherapy was described to successfully treat ASPD in one case report. The
patient’s usual sleep time of 6:30 p.m. was slowly advanced to 11 p.m. over 2 weeks
by advancing his sleep time 3 h every 2 days. The patient was able to maintain his
new sleep time of 11 p.m. after he left the hospital for 5 months [47]. Chronotherapy
has not been studied further, however, and practicality may limit its clinical use.
While melatonin administration has been shown to phase delay circadian
rhythms, no studies have examined its efficacy in ASPD [48]. Melatonin adminis-
tered in the morning should phase delay the sleep/wake rhythm and would be ideal
for patients with ASPD. Clinicians should be aware of its soporific effect and potential
for morning drowsiness with administration. Given the limited treatment options
for ASPD, however, melatonin is a potential therapeutic option that should achieve
higher compliance rate than chronotherapy or bright light therapy.

Free-Running Type

When the endogenous circadian rhythm cannot be entrained by the light–dark cycle,
the rhythm will free run. Since the human free-running circadian period is usually
>24 h, the sleep–wake cycle gradually drifts each day. This is often observed in
blinded individuals whose retinohypothalamic tract does not transmit light and dark
signals to the SCN [49]. Approximately 50% of blinded individuals have disturbed
sleep [50, 51]. Rarely, sighted individuals are affected as well [52, 53].

Diagnosis of Free-Running Type

Individuals with a free-running type circadian rhythm disorder will exhibit short
periods of normal sleep duration alternating with longer periods of short sleep,
excessive daytime sleepiness and daytime napping [53, 54]. Symptoms may be less
severe in individuals who time their sleep–wake cycle to correspond with their
endogenous, free-running rhythm. Diagnosis is based on a detailed sleep history
284 B.S. Lu et al.

suggestive of a gradual delay in the sleep–wake cycle [55]. Sleep diaries and
actigraphy can be helpful in establishing the diagnosis [29, 56].

Treatment of Free-Running Type

Although light is the strongest synchronizer of the circadian clock, non-photic signals
also can entrain the endogenous circadian rhythm. Exogenous melatonin, exercise,
timing of meals, and an imposed sleep–wake schedule can also entrain the circadian
rhythm, albeit weakly compared to light [49]. Therefore it seems reasonable that
adhering to a scheduled sleep–wake routine with scheduled meals during the day
will promote entrainment to a 24 h period in free-running individuals, although
there is no published evidence to support this assertion.
Exogenous melatonin has been reported to entrain free-running individuals [51,
53, 57]. As mentioned above, the free-running sleep–wake cycle gradually delays,
and free-running individuals intermittently experience a temporary period of normal
sleep. During this period of normal sleep, daily administration of low dose melatonin
0.5 mg at bedtime (during the advance phase of the melatonin phase-response curve)
can successfully entrain the circadian rhythm to a 24 h period [49, 58]. The efficacy
of melatonin-receptor agonists, such as ramelteon and agomelatine, in free-running
type is currently unknown.

Irregular Sleep–Wake Rhythm

An irregular sleep–wake pattern is characterized by the absence of an observable

circadian rhythm where three or more short periods of sleep and wake are randomly
dispersed throughout the 24 h period. Typically, each of the sleep and wake periods
lasts for approximately 1–4 h. The prevalence of irregular sleep–wake rhythm is
higher in older adults and is attributed to a variety of factors including an age-
related reduction in circadian neuronal activity, decreased sensitivity and exposure
to light, and reduced daytime physical and social activity [59]. Older individuals
with neurodegenerative disorders, such as Alzheimer’s disease, and who are institu-
tionalized due to poor physical health are at higher risk for irregular sleep–wake
rhythm [59]. Individuals with traumatic brain injury and mental retardation may
also be at increased risk [59].

Diagnosis of Irregular Sleep–Wake Rhythm

A clinical history of fragmented, short sleep interspersed with short periods of wake
is suggestive of an irregular sleep pattern. Reports of insomnia during the night and
excessive sleepiness and frequent napping during the day are common. There should
be three or more short sleep and wake periods throughout a 24 h period, each lasting
15 Circadian Disorders 285

for only several hours [55]. A sleep diary or actigraphy for 1–2 weeks can be helpful
in establishing a diagnosis [29, 56]. A detailed sleep evaluation to determine the
presence or absence of other sleep disorders, such as sleep disordered breathing, is
essential in these patients.

Treatment of Irregular Sleep–Wake Rhythm

In order to promote sleep consolidation at night and wakefulness during the day,
enhancing exposure to a variety of time cues is essential. These cues include a regularly
scheduled bedtime and wake time, light therapy during the day, exogenous melatonin
at bedtime, and scheduled physical and social activities. Structured daytime physical
and social activities as well as a scheduled sleep and wake routine can promote consoli-
dated nighttime sleep and improve daytime wakefulness [60]. Since light is the strongest
time cue, maximizing bright light exposure during the daytime can decrease daytime
napping and promote consolidated sleep. In one study, bright light therapy for 2 h in the
morning improved nighttime sleep and reduced daytime sleeping in patients with
dementia [61]. Exogenous melatonin at bedtime when combined with light therapy
may promote consolidated nighttime sleep [62]; however, the efficacy of melatonin
alone has not been consistent [63–65]. One study showed that melatonin plus light
therapy was associated with improved sleep and cognitive performance in elderly sub-
jects with dementia; however, melatonin treatment without light therapy was associ-
ated with withdrawn behavior and mood disturbance [66]. Until more research is
available, it seems reasonable that for most elderly patients with dementia, melatonin
should be used in combination with bright light therapy rather than alone. Avoidance
of light and loud noise in the late evenings and nighttime is recommended [67].

Shift Work Disorder

Shift work sleep disorder occurs when the patient’s work schedule overlaps with the
normal sleep cycle. In certain individuals, this overlap may result in excessive sleep-
iness during work hours and insomnia when attempting to sleep during off hours.
Studies suggest that sleep is shortened by 2–4 h in night shift workers compared to
day workers with a reduction in stage 2 and stage REM sleep [68, 69]. This is likely
due to a heightened alerting signal from the endogenous circadian clock interfering
with day sleep. Consequently, shift workers often suffer sleep disruption and are at
increased risk for excessive sleepiness during work, errors in judgment, impaired
job performance, and serious accidents compared to day workers [70–72].
Approximately 20% of the workforce in industrialized countries are shift workers,
and one study estimated that the prevalence of shift work sleep disorder is 10%
among night and rotating workers [73]. Rotating shift workers may be at increased
risk for shift work disorder compared to night workers, presumably from lack of
adjustment to a fixed schedule [74].
286 B.S. Lu et al.

Diagnosis of Shift Work Disorder

Sleep disturbances and sleepiness are common in shift workers. It has been reported
that 40–80% of night and rotating shift workers suffer sleep complaints [55], but not
all of these complaints are necessarily secondary to shift work. Therefore an impor-
tant challenge facing clinicians is to distinguish those who have excessive sleepiness
and insomnia due to shift work intolerance and those who have sleep complaints
related to a separate sleep disorder. Obtaining a detailed sleep history for symptoms
of sleep disordered breathing, other hypersomnia and insomnia disorders, and
movement disorders such as restless legs syndrome is critical [74].
Common symptoms of shift work disorder are excessive sleepiness at work and
insomnia or insufficient sleep between shifts. Problems with performing work duties
and falling asleep during work shifts are frequently present [74]. Social relationships
of shift workers may be strained from misalignment of work and sleep schedules
with day-oriented social and family schedules [75]. Gastrointestinal complaints,
such as irritable bowel syndrome and peptic ulcer disease, are also more prevalent
in shift workers [73, 76, 77]. Although sleep disturbance and fragmentation may be
present, more commonly shift workers complain of shortened or insufficient sleep
[78]. In addition to a detailed history, sleep diaries or actigraphy may be useful in
establishing the diagnosis of shift work disorder by demonstrating shortened sleep
or sleep disruption between work shifts [29, 56].

Treatment of Shift Work Disorder

The approach to treating shift work disorder should be multi-faceted and tailored to
the patient’s needs, preferences, family and social responsibilities, and work schedule.
There are three main strategies that warrants review: (1) Improve circadian alignment
with sleep and shift work schedules; (2) improve sleep (using cognitive-behavioral
therapy, melatonin, and hypnotics); and (3) enhance alertness with scheduled naps
and wake-promoting agents.
The first strategy is to improve circadian alignment with work and sleep schedules.
Because the primary underlying etiology of shift work disorder is circadian mis-
alignment, strategies to realign the circadian clock with the sleep/wake/work schedule
may reduce excessive sleepiness during shift work and improve sleep. Since light is
the strongest synchronizing agent for the circadian clock, appropriately timed expo-
sure to bright light can help accelerate and maintain circadian alignment in shift
workers [34, 79]. In night shift workers, the goal is to delay circadian rhythms so
that the sleep period occurs during the day and wakefulness is maintained during the
night work period. This is referred to as adaptation [80]. A number of studies have
shown that several hours of either intermittent or continuous light exposure ranging
from 2,500 to 9,500 lx given during the night shift results in improved alertness
during the shift and accelerated circadian realignment [81–84]. One simulated night
shift study found that five light treatments (approximately 4,100 lx), each lasting
15 min and separated by 45-min intervals, were effective in delaying DLMO and
was associated with improved performance measures using the Automated
15 Circadian Disorders 287

Neurophysiological Assessment Metrics (ANAM) test battery [85]. Subjects who

did not have a significant delay in DLMO were more likely to have reduced total
sleep times [85]. In addition to increasing light levels during the night, it is also
important to avoid morning light by using goggles or sunglasses in the morning
following the night shift, because exposure to light in the early morning could
advance the timing of circadian rhythms and prevent adaptation [84–86]. However,
for many shift workers, the demands of job responsibilities may render light therapy
inconvenient and unfeasible, and adequate light sources may not be widely available.
The second strategy is to improve sleep quality and increase sleep time with
behavioral strategies and medications. Adherence to principles of good sleep
hygiene and treatment of comorbid sleep disorders, such as insomnia, sleep apnea,
and restless legs, are essential. Good sleep hygiene includes adhering to a regular
wake and sleep schedule, daily exercise, and avoiding excessive caffeine, nicotine,
and alcohol close to bedtime [87]. These healthy behaviors can help improve sleep
quality, maintain circadian alignment, and prevent the development of factors that
precipitate and perpetuate insomnia.
A number of studies have evaluated the use of hypnotics on sleep under simu-
lated shift work conditions. Although several hypnotics, such as zopiclone [88, 89],
triazolam [90], and zolpidem [91–93] have been shown to improve daytime sleep
quality in some subjects, these medications are not approved by the U.S. Food and
Drug Administration (FDA) for this purpose. Use of these medications should be
done with caution given the potential adverse consequences of long-term hypnotic
use and carryover sedation. Melatonin, on the other hand, has a largely benign safety
profile. Exogenous melatonin (1–3 mg), when given before bedtime, has been
shown to modestly improve day sleep quality and duration in some but not all shift
workers [29, 83, 94]. Although melatonin has not been approved by the FDA for the
treatment of CRSD, exogenous melatonin is generally well tolerated with only mild
side effects. The most commonly reported side effects include drowsiness, fatigue,
and nausea [95].
The third strategy and perhaps from a functional and safety perspective is to
enhance alertness with scheduled naps and when needed wake-promoting agents.
Scheduled naps have been shown to be effective in reducing sleepiness in shift
workers. An afternoon 1–2 h nap prior to a night shift and short naps during the
work shifts can reduce sleepiness and improve cognitive function [96–99]. Shorter
naps of 10–20 min are typically recommended to avoid the grogginess that accom-
pany longer sleep periods, although the optimal amount of nap time needed has not
been established and likely varies depending on the individual [96, 97, 100].
Caffeine is a widely available and inexpensive medication that is effective in
improving wakefulness in shift workers. Studies have shown that 150–400 mg of
caffeine reduces sleepiness, increases subjective alertness, and improves perfor-
mance during the night shift [101]. The effectiveness of caffeine is enhanced when
combined with naps [102]. Modafinil is a wake-promoting medication approved by
the FDA for excessive sleepiness in shift workers. Studies have shown that modafinil
improves alertness and quality-of-life scores in shift workers and is generally well
tolerated [103–105]. Headache and nausea are the most common side effects, and
serious side effects are rare. However, there is one published case report of a woman
288 B.S. Lu et al.

with no previous psychiatric history, who developed psychosis while taking

modafinil under simulated shift work conditions [106]. Recently, armodafinil
(containing the R-isomer of modafinil only, giving rise to more sustained action
instead of both R and S isomers as in modafinil) 150 mg 1 h before shift work was
shown to improve wakefulness, increase mean sleep latency and improve neurocog-
nitive function in permanent night and rotating shift workers [107]. However, it is
important to note that although wake-promoting medications improve function,
alertness level does not normalize and many workers remain excessively sleepy
during the work shift. Therefore, adherence to good sleep hygiene, behavioral and
environmental approaches to enhance circadian alignment, as well as counseling on
safety precautions are essential for all patients.

Jet Lag

Jet lag occurs when the endogenous circadian rhythm becomes misaligned with the
external light–dark cycle due to travel across time zones. Symptoms are generally
temporary and include nighttime insomnia and excessive daytime sleepiness.
International travel across transmeridian lines is common. In 2007, it was reported
that 31 million U.S. travelers went overseas, many to Europe and Asia [108]. Jet lag
can have adverse effects on alertness, mood, and cognitive and physical perfor-
mance, which have important consequences for travelers involved in the fields of
business, military, and athletics [109–113].

Diagnosis of Jet Lag

The symptoms of jet lag are often predictable depending on the direction of travel.
Individuals flying east develop symptoms similar to delayed sleep phase. Difficulty
falling asleep in the evenings and excessive sleepiness in the mornings is common.
Conversely, individuals flying west develop symptoms similar to advanced sleep
phase and include excessive sleepiness in the early evenings and early awakenings
in the middle of the night or morning. Symptoms are temporary and eventually
wane as the endogenous circadian rhythm adjusts to the external light–dark cycle.
Symptoms of jet lag are generally more pronounced and adjustment prolonged for
eastward travelers compared to westward travelers. This is because the endogenous
circadian rhythm is >24 h, and it is easier to adjust to westward travel by phase
delay as opposed to eastward travel, which requires a phase advance [55].

Treatment of Jet Lag

Symptoms of jet lag improve as the endogenous circadian rhythm gradually adjusts
to the external environment. Treatment of jet lag involves accelerating this adjustment
15 Circadian Disorders 289

with appropriately timed exposure to light and melatonin as well as a number of

behavioral strategies. Behavioral strategies include avoiding excessive caffeine and
alcohol during travel to reduce travel fatigue, eat meals at local times, and engage
in good sleep hygiene [114].
For eastward travelers, appropriately timed exposure to light and melatonin to
advance the endogenous circadian clock will accelerate alignment and improve
symptoms of jet lag. Early morning light exposure and avoidance of light in the
evenings will promote advancement of the circadian rhythm [114]. Melatonin
0.5–5 mg taken at bedtime local time may also promote advancement of the endoge-
nous circadian clock [115, 116]. Advancing the endogenous circadian clock prior to
traveling east has also been proposed as a strategy to reduce jet lag symptoms [117,
118]. In one study, subjects advanced their typical morning wake up times by 1 or 2 h
each day for 3 days [118]. During those 3 days after awakening, subjects were exposed
to a total of 2 h of light treatments (four 30 min treatments at approximately 5,000 lx
separated by 30 min of ordinary room light) [118]. Phase advancement of approximately
1.4–1.9 h was achieved [118]. Although this was not a field study, phase advancement
prior to eastward travel may significantly reduce jet lag symptoms [118].
For westward travelers, appropriately timed exposure to light and melatonin to
delay the endogenous clock will accelerate alignment. Maximizing light exposure
in the evenings and avoiding morning light will promote a delay in the circadian
rhythm. Melatonin in the mornings may also accelerate circadian delay but may
result in sleepiness during the day. The soporific effects of melatonin may limit its
use in this setting [108].
Symptomatic treatment of insomnia symptoms and excessive daytime sleepiness
secondary to jet lag with naps, caffeine, hypnotic, and wake-promoting medications
may also be useful. In order to improve sleep, 5 mg of melatonin for 4 days at bedtime
local time has been shown to be beneficial [116, 119]. Zolpidem has also been
shown to reduce symptoms of sleep disturbance [120, 121]. In subjects traveling
east over five time zones, ramelteon, a melatonin-receptor agonist, given at bedtime
was demonstrated to reduce sleep latency compared to placebo [122]. Caffeine has
been shown to improve wakefulness during the day in the setting of jet lag [119]. In
subjects flying eastward from the U.S. to France (6 h time zone change), armodafinil
150 mg was demonstrated to be effective in improving wakefulness during the day
and modestly increased mean sleep latency compared to placebo [123]. Headache,
nausea, and diarrhea were the most common side effects [123].

Summary

Among its influence on many physiological functions, the circadian system regu-
lates the sleep/wake cycle. CRSDs result from alterations in the endogenous circa-
dian system or misalignment of the endogenous circadian rhythms with the external
environment. Although treatment of CRSDs can include pharmacotherapy, lifestyle,
and behavioral changes to optimize circadian alignment and sleep quality are essential
290 B.S. Lu et al.

for everyone. Recent molecular research has shed light on genetic causes of CRSDs
that may lead to novel and targeted therapeutic options for these under-recognized
disorders.

Summary of Keypoints

• The sleep/wake cycle is the most outward display of circadian rhythm generated
by the master clock in the brain. CRSDs can occur when the timing of the central
clock is out of synchrony with the conventional schedule (e.g., sleep phase dis-
orders, free-running, irregular sleep wake rhythm) or when there is misalignment
between the normal intrinsic rhythm and the 24-h external environment (e.g., jet
lag and shift work). The most commonly encountered CRSDs are the sleep phase
disorders (advanced and delayed), shift work sleep disorder and jet lag disorder.
• Sleep phase disorder are characterized by inability to initiate sleep or wake up at
conventional times, resulting in insomnia or daytime sleepiness which interferes
with the patient’s life. Genetic polymorphisms of clock genes have been discovered
in patients.
• Treatment of delayed and ASPD involves advancing or delaying the sleep phase
with bright light therapy and/or melatonin, as well as behavioral changes. Specific
timing of bright light and melatonin therapy is dependent on the phase of each
patient’s circadian rhythm.
• Shift work sleep disorder occurs when the patient’s work schedule overlaps with
the normal sleep cycle, resulting in excessive sleepiness during work hours and
insomnia when attempting to sleep during off hours.
• Management of shift work sleep disorder involves improving circadian align-
ment with sleep and shift work schedules, improving sleep with behavioral therapy,
melatonin, and hypnotics, and enhancing alertness with scheduled naps and
wake-promoting agents.
• Jet lag can have adverse effects on alertness, mood, and cognitive and physical
performance, and symptoms are generally more pronounced and adjustment
prolonged for eastward travelers compared to westward travelers.
• Symptoms of jet lag can potentially be mitigated by pre-travel phase shifting
with bright light therapy so that the sleep/wake cycle is more aligned to day and
night at destination. Alternatively, bright light and melatonin therapies can be
used upon arrival.

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Chapter 16
Narcolepsy and Idiopathic Hypersomnia

Imran Ahmed and Michael Thorpy

Keywords Narcolepsy • Idiopathic hypersomnia • Symptoms • Epidemiology

• Pathophysiology • Diagnosis • Differential • Pediatric • Treatment

Introduction

Excessive daytime sleepiness (EDS) is a common symptom that is part of many

different medical, neurologic, psychiatric, and sleep disorders. The terms “excessive
daytime sleepiness” and “hypersomnia” are often used interchangeably; however,
the term “hypersomnia” should be reserved to refer to a group of disorders in which
the primary complaint is excessive sleepiness. Two of these disorders, narcolepsy
and idiopathic hypersomnia, are considered to be hypersomnias of central origin
and will be discussed here.
Narcolepsy was originally described by Gelineau in 1880 as a disorder involving
excessive sleepiness and sleep attacks associated with a variety of emotional states.
He also described episodes of falls or “astasia” which was later termed cataplexy.
Since this time (especially over the last 5 years), a number of advances in our
understanding of narcolepsy have been made. For instance, the discovery of the
association between narcolepsy and the Human Leukocyte antigens (HLA)
DRB1*1501/DRB1*1503 and with DQB1*0602 suggested an autoimmune
process. Also, the discovery by two independent groups in 2005 of a reduction in
the neuropeptide, hypocretin/orexin, is believed to be responsible for many of the
symptoms of narcolepsy. Additionally, in 2005, the International Classification of

I. Ahmed • M. Thorpy (*)

Sleep-Wake Disorders Center, Montefiore Medical Center,
111 East 210th Street, Bronx, NY 10467, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 297
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_16,
© Springer Science+Business Media, LLC 2012
298 I. Ahmed and M. Thorpy

Sleep Disorders, second edition (ICSD-2) categorized narcolepsy into three

different types: narcolepsy with cataplexy, narcolepsy without cataplexy, and
narcolepsy due to a medical disorder. The ICSD-2 characterized narcolepsy by
symptoms of excessive sleepiness as well as the pathologic manifestations of REM
sleep, such as cataplexy, sleep paralysis, and hypnagogic hallucinations.
The term “idiopathic hypersomnia” was first used in 1976 by Bedrich Roth to
describe a disorder with both a monosymptomatic and a polysymptomatic form.
The monosymptomatic form exhibits only EDS, whereas the polysymptomatic form
manifests not only symptoms of EDS, but also a long duration of the major sleep
period, and a prominent sleep inertia upon awakening. Unlike narcolepsy, there is
relatively limited research on the pathophysiology or the spectrum of symptoms of
idiopathic hypersomnia. In 2005, the ICSD-2 classified idiopathic hypersomnia into
two types, one associated with a prolonged sleep episode at night, which is called
idiopathic hypersomnia with long sleep time, and another that has a normal duration
of sleep at night called idiopathic hypersomnia without long sleep time.

Clinical Features

Narcolepsy

Narcolepsy is described as a syndrome consisting of EDS (including periods of

irresistible sleep), cataplexy, sleep paralysis, and hypnagogic hallucinations;
additional features include automatic behaviors and fragmented or disrupted
nighttime sleep. The effects of narcolepsy are largely manifested during periods
of wakefulness, i.e., features of REM sleep intrude into wakefulness.
Narcolepsy typically begins with the symptom of excessive sleepiness and other
symptoms of variable severity can develop slowly, suddenly, or not at all. Occasionally,
cataplexy can develop first and then later be followed by the development of excessive
sleepiness; this is especially true in children, where sleepiness is disguised as behavioral
abnormalities [1]. Narcolepsy patients often have an irresistible urge to sleep, which
often occurs at inopportune times whether it is during monotonous sedentary tasks or
while performing mentally or physically demanding activities. For instance, they can
fall asleep while eating, while sitting at a meeting, during phone conversations, during
sexual intercourse, or while driving a car. These sleep episodes occur about 3–5 times/
day in most patients and usually vary from a few minutes to several hours in duration
[2]. Patients often report that after these sleep episodes or after taking scheduled naps,
they wake up feeling refreshed and may not feel sleepy again for up to a few hours
later; however, there are also many patients who indicate persistent (although perhaps
somewhat improved) sleepiness despite taking these naps. Patients can also experience
microsleep events, which are seconds or less of sleep that intrude into the waking state.
Upon awaking from these episodes, the patients may not be aware that they were
16 Narcolepsy and Idiopathic Hypersomnia 299

asleep and continue the activity they were performing prior to the sleep event. It is
likely that such episodes are at least partially associated with patients’ complaints of
difficulty concentrating, inattention, or memory impairment.
In children, it is difficult to identify classic narcolepsy symptoms since many are
not able to provide an accurate history of cataplexy, hypnagogic hallucinations, or
sleep paralysis. Sleepiness may also manifest as behavioral problems, decreased
performance, inattentiveness, lack of energy, or bizarre hallucinations that makes it
even more difficult to diagnose narcolepsy. Furthermore, when excessive sleepiness
is present, it can often be mistaken for normal behaviors in children of preschool
age, as they usually take habitual naps. Occasionally in school-aged children, exces-
sive sleepiness can be identified when there is a reappearance of daytime naps in a
child who had previously discontinued regular napping [3].
Cataplexy is the most specific symptom of narcolepsy consisting of an abrupt,
bilateral (occasionally unilateral) loss of skeletal muscle tone. It is usually triggered
by the occurrence of sudden emotion such as laughter or humorous experiences;
sometimes even the memory of a humorous event can precipitate an attack. Other
triggers for cataplexy include anger, embarrassment, surprise, stress, or even sexual
arousal [4]. During a cataplexy attack, which can last up to several minutes, the
patient is unable to move; however, the diaphragm and ocular muscles are unaffected.
During this time, the patient remains awake, aware of their surroundings and able to
remember the details of the event. If the attack is prolonged, however, sleep can
follow. More commonly, attacks of cataplexy are partial, affecting only certain mus-
cle groups, such as the arms, neck, or face. During partial cataplexy attacks, the jaw
may sag, the head can droop, and speech may become garbled [5]. In children,
atypical manifestations of cataplexy can include blurred vision, irregular breathing,
sudden loss of smiling, or “semipermanent eyelid and jaw weakness” [6].
Sleep related hallucinations, sleep paralysis, and automatic behaviors are
common manifestations of many disorders that disrupt/fragment sleep and cause
excessive sleepiness, including narcolepsy and idiopathic hypersomnia [7]. Similar
to cataplexy, patients with sleep paralysis experience a brief loss of voluntary
muscle control with an inability to move or speak, but retain awareness during the
event. Unlike, cataplexy, these episodes are not provoked by intense emotion or
stress. The phenomena usually occur during sleep–wake transitions and are often
associated with fearful hypnopompic or hypnagogic hallucinations. The events
typically remit on their own within 1–10 min, but can also be terminated when
someone touches the patient [8].
The hypnagogic and hypnopompic hallucinations can also occur independently
of the sleep paralysis episodes. They are intense dream-like states that occur when
falling asleep (hypnagogic) or when awaking from sleep (hypnopompic) [8]. The
hallucinations are usually visual or auditory and occasionally involve other senses,
e.g., tactile or vestibular. They are occasionally pleasant, but quite often frightening
or disturbing to the patient. The visual hallucinations can consist of simple forms,
such as circles or multisided geometric figures or can be more intricate such as
animals or people. Similarly, the auditory hallucinations can manifest as simple
300 I. Ahmed and M. Thorpy

sounds, such as knocking on a door or a phone ring, or more complex tunes, such as
a musical composition. Less often, patients report hallucinations such as smelling a
scent/odor, or having a sense that one is falling, or feeling that someone or
something is touching them.
Automatic behavior is the performance of simple or complex routine tasks by
individuals who remain unaware of the activity. These behaviors range from activities
such as talking on the phone or writing to walking, cooking, or driving. Some
patients report that they have ordered items through the phone, or cooked a meal,
and did not remember doing so. Some also report driving home from work and not
realizing how they got there. The personal and public hazards of such behaviors are
self-evident.
In addition to episodes of EDS, narcolepsy patients also report difficulty in
maintaining sleep at night due to a dysfunction of central sleep regulation which
causes frequent transitions between sleep and wakefulness throughout the entire
24-h cycle. They report frequent nocturnal awakenings and occasionally indicate
that they do not sleep for long periods during the night.

Idiopathic Hypersomnia

Similar to narcolepsy, patients with idiopathic hypersomnia also have symptoms of

excessive sleepiness. Those with the long sleep time type have a prolonged major
sleep period of 10 h or longer with few or no awakenings. They report often having
an irresistible urge to take prolonged naps (up to 3–4 h in duration) during the day
and typically awaken unrefreshed. These patients also experience difficulty waking
up in the morning and at the end of a nap [3, 7, 9].
Analogous to idiopathic hypersomnia with long sleep time, patients with idio-
pathic hypersomnia without long sleep time have symptoms of excessive sleepi-
ness. They also take prolonged nonrefreshing naps and have difficulty awaking
from sleep periods, albeit it is typically less laborious than in the long sleep time
type. The duration of the major sleep period in these patients, however, although
occasionally prolonged is by definition less than 10 h [3, 6, 9].
In a report by Bassetti and Aldrich in 1997 [9], some patients with idiopathic
hypersomnia with and without long sleep time were noted to have orthostatic
hypotension, headaches, as well as cold hands and feet (Raynaud’s type phenom-
ena). Additionally, as mentioned earlier, hypnagogic hallucinations and sleep
paralysis may be present. These patients often never feel fully alert, even after their
normal or prolonged sleep period. They often require multiple alarm clocks to
awaken in the morning or after naps, but usually end up becoming dependent on
other people to awaken them. The difficulty awakening is followed by, or is at least
partially attributed to, a state of sleep drunkenness. Simply stated, sleep drunken-
ness is the confusion and behaviors a normal person may experience if abruptly
awoken from deep sleep. Patients are confused upon awakening and are unable to
perform tasks or react appropriately [7, 9].
16 Narcolepsy and Idiopathic Hypersomnia 301

Epidemiology

Narcolepsy

Due to the overlap of clinical symptoms and polysomnographic/multiple sleep

latency test (MSLT) features with other conditions such as depression, other sleep
disorders or even with normal individuals, it is difficult to make an accurate assess-
ment of the true prevalence of narcolepsy. It is estimated that less than 50% of
patients with narcolepsy have been diagnosed [10, 11]. Nevertheless, narcolepsy
has been documented to begin at any age from infancy (rarely) to as late as old age,
but most commonly within the first two decades of life. It affects both men and
women equally with an approximate prevalence of 1 in 2,000 people (0.05%) in the
United States [12].
There appears to be a genetic, racial, and ethnic predisposition for the
development of narcolepsy [13]. The risk of a first-degree relative developing
narcolepsy with cataplexy is approximately 1–2%, which is prominently higher
than that estimated for the general population [14]. In addition, the HLA subtypes
DR2 (DRB1*1501) and DQ (DQB1*0602) have also been found to be closely
associated with narcolepsy. The HLA marker, DQB1*0602 has a prevalence
ranging from 85 to 95% in patients with narcolepsy with cataplexy and about 40%
in patients with narcolepsy without cataplexy vs. about 26% in the general popula-
tion [15]. A review of the literature indicates that the prevalence of narcolepsy/
cataplexy ranges from a low of 0.002% among Israeli Jews to a high of 0.15%
among the Japanese general population. More recently, a general population study
with a representative sample of over 18,000 subjects in five European countries
estimated a prevalence of 0.047% [3].
The prevalence of cataplexy among patients with narcolepsy varies widely with
estimates ranging from 60 to 90% [16] of narcoleptics. Patients with cataplexy gen-
erally report that this symptom remains persistent with only minor fluctuations in
severity; however, the severity and frequency of attacks may vary widely and range
from occasional to multiple attacks daily. A few patients have reported spontaneous
remission of cataplexy attacks. It has been suggested that a decline in cataplexy over
time represents the ability of patients to adapt to their illness and learning to avoid
those situations where cataplexy is most likely to occur.

Idiopathic Hypersomnia

More challenging than assessing the prevalence of narcolepsy is that of determining the
prevalence of idiopathic hypersomnia. The reported prevalence in clinic populations
when compared to narcolepsy patients widely varies depending upon the literature
reviewed [6, 17–19]. At least part of the difficulty in determining idiopathic hypersom-
nia’s prevalence is due to its nosological ambiguity. There has also been a propensity
302 I. Ahmed and M. Thorpy

to label all difficult-to-classify cases of EDS as idiopathic hypersomnia [20]. Since the
ICSD-2 classification scheme was developed, there have not been any systematic
prevalence studies for idiopathic hypersomnia. Accordingly, it is safe to say that the
true prevalence of idiopathic hypersomnia is unknown. What we do know is that
there appears to be a female predominance [21] with the age of onset ranging from
birth to early adulthood [22]. Some earlier studies also suggest an autosomal domi-
nant mode of inheritance [23].

Pathophysiology

Narcolepsy

As mentioned earlier, there is a higher occurrence of HLA DQB1*0602 in narco-

lepsy patients than in the general population. It is suspected that patients with this
HLA marker (and likely other currently unknown genetic links) may possess a
genetic susceptibility for some event that leads to the development of narcolepsy.
Environmental factors such as infections [24, 25], head trauma [26], or even a
change in sleeping habits [25] have been associated with the onset of narcolepsy.
The discovery of the neuropeptide hypocretin [27, 28] has greatly enhanced our
understanding of the pathophysiology of narcolepsy. Hypocretin-containing neurons
are located in the perifornical and lateral hypothalamus where they project widely to
communicate with numerous brain nuclei including those responsible for the regula-
tion of sleep, alertness, and muscle tone. Evidence suggests that most cases of narco-
lepsy with cataplexy are associated with loss of hypocretin-containing hypothalamic
neurons and cases of narcolepsy without cataplexy may be caused by a partial loss
of these neurons. Thannickal et al. [29] and Mignot et al. [30] reported an 85–95%
loss of hypocretin-containing neurons in narcolepsy with cataplexy patients that
corresponded to the finding of low or undetectable concentrations (£110 pg/mL) of
hypocretin in the cerebrospinal fluid (CSF) of these patients. More recently, Thannickal
et al. [31] found a loss of about a third of the hypothalamic hypocretin-containing
cells in one patient with narcolepsy without cataplexy. An autoimmune process may
be responsible for the loss of the hypocretin neurons; however, antibodies to hypocretin
and hypocretin receptors have not been found [32–35].
Recently, additional support for the autoimmune etiology hypothesis was dis-
covered. Increased antistreptococcal antibodies were reported in patients with recent
onset of narcolepsy, suggesting streptococcal infections may be an inciting event
that is initiating an autoimmune process [24, 36]. Hallmayer et al. [37] also found a
strong association between narcolepsy and a polymorphism in the T-cell receptor
alpha locus (another indication that an autoimmune process has a role). Earlier in
2010, elevated Tribbles homolog 2 (Trib2) specific antibodies levels were discov-
ered in patients with narcolepsy. Trib2 was previously known as an autoantigen in
autoimmune uveitis; it has been identified in hypocretin neurons of a transgenic
mouse model. In narcolepsy patients, titers of Trib2-specific antibodies were highest
soon after narcolepsy onset and then decreased within the first 3 years of the
16 Narcolepsy and Idiopathic Hypersomnia 303

disorder and finally stabilized at levels much higher than that of controls (normal
controls and patients with idiopathic hypersomnia, multiple sclerosis, or other
inflammatory neurologic disorders) [38]. This finding provides exciting evidence
that narcolepsy is an autoimmune disorder; however, more work needs to be done to
establish a causal pathogenic role of the antigen and antibodies.

Idiopathic Hypersomnia

In comparison to narcolepsy, less is known about the pathophysiology of idiopathic

hypersomnia with or without long sleep time. One possible reason for this is that
there are no specific criteria, clinical or polysomnographic, that is pathognomic or
even partially characteristic of the disorder, such as cataplexy or sleep onset REM
periods are for narcolepsy. There is no clear association with CSF hypocretin levels
[39] as in narcolepsy. Although there appears to be a strong genetic component
suggested by the high proportion of familial cases, no associated genes have been
identified. Studies with HLAs have also found no connection [9].
Some early studies suggested that monoamine metabolites had a role in the
etiology of idiopathic hypersomnia [40–42] and more recently, Bassetti et al. [43]
have revisited the possible association of dopamine with idiopathic hypersomnia;
however, further studies to assess the validity of these hypotheses need to be done.
There is a possible common pathway between the pathophysiology of narco-
lepsy and idiopathic hypersomnia. A low CSF histamine level has been identified in
both these disorders and has not been seen in patients with excessive sleepiness due
to sleep apnea [44, 45]. Accordingly, it is hypothesized that low histamine may be
specific to hypersomnias of central origin [45]. In addition, since idiopathic hyper-
somnia hypocretin levels are normal, it has been suggested that factors other than
hypocretin deficiency are the cause of these low histamine levels. Further research
still needs to be done to validate this hypothesis and to better understand the role of
histamine in these disorders.

Diagnosis

Narcolepsy

There are three main types of narcolepsy: narcolepsy with cataplexy, narcolepsy
without cataplexy, and secondary narcolepsy (Table 16.1). Narcolepsy with cataplexy
is defined as excessive sleepiness that occurs for at least 3 months associated with
definite cataplexy. The diagnosis may be confirmed by polysomnography followed
by a MSLT [46]. Alternatively, a low CSF hypocretin level (£110 pg/mL or one
third of mean normal control values) is diagnostic [27]. The polysomnography
should confirm at least 6 h of sleep and exclude other sleep disorders that could
account for the symptoms, such as obstructive sleep apnea syndrome. It usually
304 I. Ahmed and M. Thorpy

Table 16.1 Diagnostic criteria for narcolepsy

Narcolepsy with cataplexy
1. At least 3 months of excessive daytime sleepiness (EDS)
2. Cataplexy is present
May be confirmed by
3. PSG followed by a multiple sleep latency test (MSLT) or
a. The PSG should rule out other causes of disrupted nocturnal sleep and demonstrate at least
6 h of sleep
b. The MSLT should show a sleep latency of £8 min and two or more sleep onset REM periods
4. A cerebrospinal fluid (CSF) hypocretin-1 level £110 pg/mL
Narcolepsy without cataplexy
1. At least 3 months of EDS
2. Cataplexy is absent; however, questionable or atypical cataplexy-like episodes can be present
Must be confirmed by
3. PSG followed by a MSLT
a. PSG rules out other causes of disrupted nocturnal sleep and demonstrates at least 6 h of sleep
b. MSLT shows a sleep latency of £8 min and two or more sleep onset REM periods
Narcolepsy due to a medical condition
1. At least 3 months of EDS
2. A significant underlying medical or neurologic condition accounts for the daytime sleepiness
3. A definite history of cataplexy is present or
4. If cataplexy is absent and/or questionable or atypical cataplexy-like episodes are present then
a PSG followed by a MSLT should be done
a. PSG rules out other causes of disrupted nocturnal sleep and demonstrates at least 6 h of sleep
b. MSLT shows a sleep latency of <8 min and two or more sleep onset REM periods
5. If either condition 3 or 4 above is not met, CSF hypocretin-1 levels must be £110 pg/mL (or
30% of normal control values) in a noncomatosed patient
Adapted from American Academy of Sleep Medicine [3]

demonstrates a short sleep latency and fragmented nocturnal sleep and may show
early REM sleep onset and increased stage 1 sleep [47]. The MSLT should exhibit
two or more sleep onset REM periods with a mean sleep latency of £8 min [3].
Patients who do not have cataplexy or have atypical cataplexy-like events, and
other sleep disorders have already been excluded, require confirmatory sleep
studies, i.e., nocturnal polysomnography followed by an MSLT, for the diagnosis.
CSF hypocretin-1 levels are usually normal in these patients [18, 27]; therefore, it
is usually not indicated. CSF hypocretin-1 levels may be done, however, for patients
with atypical cataplexy-like episodes for whom a diagnosis of narcolepsy with cata-
plexy is being entertained. It can also be done for pediatric patients with suspected
narcolepsy, especially if the MSLT is inconclusive, to make the diagnosis. Such
studies are also required to establish the diagnosis of secondary narcolepsy that
temporally occurs with an underlying neurological disorder.
As mentioned earlier, it is difficult to identify classic narcolepsy symptoms in
children. The diagnosis can be made clinically if definite cataplexy is present or
with the assistance of the MSLT or by measurement of CSF hypocretin-1 levels.
A PSG followed by an MSLT can help objectively assess sleepiness in a child;
however, normal values on sleep studies, especially for MSLTs, have not been
16 Narcolepsy and Idiopathic Hypersomnia 305

Table 16.2 Diagnostic criteria for idiopathic hypersomnia

Idiopathic hypersomnia with long sleep time
1. At least 3 months of EDS
2. Interview, actigraphy, or sleep logs demonstrates over 10 h of nocturnal sleep with
a. Difficulty awaking in the morning
b. Difficulty awaking at the end of naps
3. PSG performed
a. Rules out other causes of sleepiness
b. Shows a short sleep latency
c. Shows a major sleep period greater than 10 h
4. MSLT, if done, shows
a. A mean sleep latency of <8 min
b. Less than two sleep onset REM periods
Idiopathic hypersomnia without long sleep time
1. At least 3 months of EDS
2. Interview, actigraphy, or sleep logs demonstrates normal sleep period (more than 6 h and not
over 10 h)
3. PSG performed
a. Rules out other causes of sleepiness
b. Shows a major sleep period that is normal in duration (more than 6 h but not over 10 h)
4. MSLT, if done, shows
a. A mean sleep latency of <8 min
b. Less than two sleep onset REM periods
Adapted from American Academy of Sleep Medicine [3]

standardized in subjects younger than 8 years of age and results should be interpreted
with care. Carskadon [48] suggested using a child’s Tanner stage of sexual develop-
ment to compare sleep study results to normal values of nocturnal total sleep time,
daytime sleep latency, and daytime REM sleep latency as these are closely linked to
the Tanner stages. As suggested earlier, HLA testing (in a child or adult) is not a
useful screening or diagnostic tool; however, it might be useful in atypical narco-
lepsy with cataplexy presentations. A negative test should encourage the physician
to make certain that other sleep disorders are excluded before assigning a diagnosis
of narcolepsy.

Idiopathic Hypersomnia

In contrast to narcolepsy, idiopathic hypersomnia has only two types: one with a
long sleep time and one without a long sleep time (Table 16.2). In order to make this
diagnosis, the associated excessive sleepiness, similar to narcolepsy, needs to occur
almost daily for at least 3 months. In patients with the “long sleep time type,” the
nocturnal sleep is more than 10 h long and there is difficulty awaking from the sleep
period including any naps. In the “without long sleep time type,” the nocturnal sleep
period is greater than 6 h but less than 10 h. Polysomnography demonstrates these
sleep times and should rule out other causes (e.g., sleep apnea) of excessive sleepiness.
An MSLT performed following the nocturnal polysomnography should show a
306 I. Ahmed and M. Thorpy

mean sleep latency of less than 8 min with less than two sleep onset REM periods
[3]. In patients with long sleep time, however, awaking the patient in the morning
following an overnight polysomnogram to do a MSLT does not allow for the documen-
tation of the prolonged sleep time. Moreover, the short naps scheduled every 2 h do
not allow for the demonstration of prolonged unrefreshing naps. Accordingly, alter-
nate nonvalidated means for diagnosis have been suggested by some authors,
including extended (24 h or longer) polysomnography or actigraphy [7]. In patients
without long sleep type, the MSLT is currently the primary way to differentiate
these patients from patients with narcolepsy without cataplexy.

Differential Diagnosis

Excessive sleepiness is common to many sleep disorders, besides narcolepsy and

idiopathic hypersomnia, and can also be a normal phenomenon in certain circum-
stances (e.g., sleep deprivation). Some of these sleep disorders can be differentiated
from narcolepsy or idiopathic hypersomnia by history. For instance, identification
of a disruptive environmental feature during sleep may lead one to the diagnosis of
an environmental sleep disorder. A history of sleeping less than expected from age-
adjusted normative data or having a sleep period that is delayed, advanced, or irreg-
ular would suggest behaviorally induced, insufficient sleep syndrome or a circadian
rhythm disorder, respectively. Psychiatric disorders (e.g., depression or substance
abuse) can also be responsible for excessive sleepiness and are identifiable on his-
tory. A description of normal sleep between episodes of hypersomnia can suggest a
diagnosis of recurrent hypersomnia.
Other disorders that cause excessive sleepiness cannot always be identified by
history alone and require additional studies to differentiate them from narcolepsy
and idiopathic hypersomnia. A polysomnogram will help identify sleep disordered
breathing in a patient. Imaging studies may discover the presence of a brain tumor
or stroke (although other findings on exam are also usually present). Blood work or
CSF analysis can help identify metabolic abnormalities or encephalitis as a cause of
the sleepiness. There was a case report by Maestri et al. [49] on a patient that was
diagnosed with idiopathic hypersomnia but after further evaluation was found to
have an insulinoma. After management of the insulinoma, his symptoms of excessive
sleepiness resolved. Another report by Shinno et al. [50] identified a patient with
idiopathic hypersomnia who was subsequently found to have subclinical hypothy-
roidism; after management with levothyroxine his sleepiness improved.
History and additional laboratory studies are also useful in ruling out disorders
that can mimic cataplexy. Transient weakness episodes can represent transient isch-
emic attacks (TIAs) if there is no history of an association with emotion or if there is
a history of vascular risk factors and/or stroke. Seizures, syncope, and brainstem or
diencephalic tumors can look like cataplexy; a positive EEG may suggest seizures;
imaging studies can help identify tumors; and a history of loss of consciousness may
help differentiate syncope or seizures from cataplexy.
16 Narcolepsy and Idiopathic Hypersomnia 307

Head Trauma and Excessive Sleepiness

Sleep disturbances, including excessive sleepiness, can occur as a result of traumatic

brain injury (TBI); accordingly, TBI should be considered in the differential diag-
nosis of excessive sleepiness. Some researchers contend that the excessive sleepiness
is due to the increased prevalence of obstructive sleep apnea and periodic limb
movement disorder that is seen in TBI patients [51]. In addition, changes in noctur-
nal sleep pattern seen in TBI patients are similar to those of depressed patients,
namely, increased nighttime awakenings and longer sleep onset latency [52]. It is
speculated that the sleepiness is due in part to this disturbed nocturnal sleep and that
treatment of concomitant mood disorders may improve the sleepiness in the TBI
patients; however, further research needs to be done in this area.
Hypothalamic damage, not necessarily visible on imaging studies, may be
responsible for the excessive sleepiness that is seen in many TBI patients. The
ICSD-2 classified this group of TBI patients under two separate categories: narco-
lepsy due to a medical condition and hypersomnia due to a medical condition (pre-
viously referred to as posttraumatic hypersomnia). A 2007 study found that the CSF
hypocretin-1 levels were decreased in these TBI patients, and a follow-up study in
2009 demonstrated the number of hypocretin neurons in the hypothalamus was sig-
nificantly reduced [53, 54]. The loss of hypocretin may be the etiology underlying
TBI associated with narcolepsy and possibly posttraumatic hypersomnia.
There is limited data on the epidemiology of excessive sleepiness in TBI patients.
In a 2001 study by Masel et al. [51], excessive sleepiness was identified in about 46%
(33 out of 71) of brain injury patients. These patients were found to have either nar-
colepsy, posttraumatic hypersomnia, sleep apnea, or other sleep disorders that were
responsible for the sleepiness. In another study, 55% (282 out of 514) of TBI patients
were identified as having sleepiness; however, the etiology of the sleepiness was not
investigated [55]. More recently, a study found subjective sleepiness to be common
in a sample of 51 TBI patients [56]. In addition, Castriotta et al. [57] reported on a
study population of 57 TBI patients of which 21% (12) demonstrated objective EDS
on MSLT studies, 3% (2) had posttraumatic hypersomnia, 5% (3) had narcolepsy,
23% (13) had obstructive sleep apnea, and 7% (4) had periodic limb movements dur-
ing sleep. Some studies suggest that the severity of the sleepiness correlates with the
severity of the TBI [55, 58]; however, other studies contradict this finding [53, 59].

Treatment

There is no known cure for either narcolepsy or idiopathic hypersomnia; however,

with respect to idiopathic hypersomnia, there are reports of spontaneous remission
[22]. For those with persistent disease, treatment is targeted at symptom management.
Even with optimum management, the EDS in narcolepsy and idiopathic hypersomnia
patients, and the cataplexy in narcolepsy patients, are seldom completely controlled.
308 I. Ahmed and M. Thorpy

Nonpharmacologic Management

Nonpharmacologic management should be initiated in all patients. Patient education

is an important component of any treatment plan. Good sleep habits with avoid-
ance of sleep deprivation and/or irregular sleep patterns should be emphasized. In
narcolepsy patients, the scheduling of short naps (15–20 min) 2–3 times/day can
help control EDS and improve alertness, but this is impractical in many settings.
Napping, in contrast, is not recommended for management of sleepiness in patients
with idiopathic hypersomnia as it usually does not help. Patients and family members
should also be warned about the potential dangers of sleepiness relative to driving
and/or in other hazardous settings. Typically, lifestyle changes alone are not enough
to adequately control the symptoms of either narcolepsy or idiopathic hypersomnia;
most patients require lifelong medication.

Pharmacologic Management of Symptoms Common

to Both Narcolepsy and Idiopathic Hypersomnia

Pharmacological management of EDS, with a few exceptions, is similar in both

narcolepsy and idiopathic hypersomnia; however, it should be noted that randomized,
double-blind, placebo-controlled clinical trials have not been done on idiopathic
hypersomnia patients. Stimulants, such as methylphenidate or dextroamphetamine,
have previously been used as first-line therapy, but more recently modafinil and
armodafinil have become the first-line treatment for most patients [60, 61]. Most
clinical studies of stimulant medications report objective improvements in sleepiness
in 65–85% of subjects.
Common adverse effects associated with stimulants include nervousness, head-
aches, irritability, tremor, insomnia, anorexia, gastrointestinal upset, and cardiovas-
cular stimulation [62]. The development of drug tolerance or addiction can also
occur; however, this risk is thought to be similar to other patient groups.
Modafanil is generally well tolerated, with headache and nausea being the most
common side effects. Armodafinil is the long acting dextro-enantiomer component
of racemic modafinil, which has equal amounts of S- and R-modafinil. It has a
similar therapeutic and side effect profile to racemic modafinil, but with the advan-
tage of having a longer elimination half-life (t½) (3–4 h for S-modafinil vs. 10–15 h
for armodafinil) [63]. Although comparative studies have not been done in narco-
lepsy or idiopathic hypersomnia, armodafinil has been shown to be effective and
produce longer wakefulness than racemic modafinil in patients with sleepiness
due to acute sleep loss [64].
Sodium oxybate, the sodium salt of gamma-hydroxybutyrate (GHB), an endog-
enous substance in the brain, is an effective medication in the treatment of daytime
sleepiness in narcolepsy [60, 65]. It has not been systematically studied in patients
with idiopathic hypersomnia. Sodium oxybate’s adverse effects include nausea (19%),
16 Narcolepsy and Idiopathic Hypersomnia 309

dizziness (18% incidence), headache (18%), nasopharyngitis (6%), somnolence (6%),

vomiting (8%), and urinary incontinence (6%) with most described as mild or mod-
erate in severity. Dizziness, nausea, vomiting, and enuresis may be dose related [66].
Currently, sodium oxybate, amphetamines, methylphenidate, modafinil, and
armodafinil are the only medications FDA approved in the United States for the
treatment of narcolepsy. Other medications have been reported to have beneficial
results, but little data is available [67]. All medications are used “off-label” for the
management of excessive sleepiness due to idiopathic hypersomnia.

Pharmacologic Management of Symptoms Specific to Narcolepsy

Cataplexy

Although treatment of sleepiness can have a mild beneficial effect on cataplexy,

most wake-promoting agents/stimulants do not provide sufficient relief from cataplexy.
Most medications used for the treatment of cataplexy have REM sleep suppressant
properties and/or increase aminergic (esp. by blocking the norepinephrine (NE)
transporter) activity [68]. Tricyclic antidepressants (TCAs), serotonin reuptake
inhibitors, and NE reuptake inhibitors have demonstrated benefit in animal studies
(which is believed to be a function of the NE reuptake inhibition). Sodium oxybate
is highly efficacious for the treatment of cataplexy in narcolepsy and is currently the
only FDA approved medication for its management.
Several small open-label studies and several decades of use have demonstrated
that the TCAs desmethylimipramine, protriptyline, imipramine, and desipramine
have beneficial anticataplectic effects [69]; however, clomipramine remains the
most widely used. Adverse events commonly associated with TCA therapy include
nausea, anorexia, dry mouth, urinary retention, and tachycardia. Men may encounter
decreased libido, impotency, or delayed ejaculation. An unusual property of TCAs
is the rebound cataplexy phenomenon that occurs upon abrupt discontinuation of
TCA therapy. When severe, this is known as status cataplecticus and can be disabling
for several days [70].
Similar to TCAs, the SSRIs including fluvoxamine, zimeldine, femoxetine,
paroxetine, and fluoxetine have all demonstrated anticataplectic activity; however,
fluoxetine appears to be the most commonly used of the SSRIs for the treatment of
cataplexy [71]. As a class, the SSRIs are generally less efficacious than TCAs;
however, they have a better safety profile and are better tolerated than the older
antidepressants. Reported adverse events include headache, nausea, weight gain,
dry mouth, and delayed ejaculation [71]. Other antidepressant medications have
also been found to have some anticataplectic activity; these include monamine
oxidase inhibitors such as phenelzine and selegiline as well as other atypical
antidepressants with pronounced NE reuptake inhibition, such as venlafaxine and
atomoxetine.
310 I. Ahmed and M. Thorpy

Fragmented Nocturnal Sleep

As mentioned earlier, sodium oxybate taken at bedtime and again during the night
increases slow wave sleep, decreases light sleep (stage N1 sleep), and decreases the
number of arousals. REM sleep is initially increased, but then decreases after
increasing dose and duration of therapy [72].
Other medications have also been tried in the management of the fragmented
sleep of narcoleptics. A study evaluating 0.25 mg of triazolam taken at bedtime
showed improved sleep efficiency and overall sleep quality, but had no beneficial
effect on daytime sleepiness [73]. Other medications such as zolpidem, eszoplicone,
or clonazepam have been used with varying success in some patients (personal
experience and conversations with other sleep medicine physicians). For symptoms
of sleep paralysis and hypnagogic hallucinations, TCAs, other REM suppressant
medications, and sodium oxybate have been successful.

Conclusion

Narcolepsy and idiopathic hypersomnia are primary central hypersomnias charac-

terized by persistent EDS. Whereas cataplexy is pathognomic for narcolepsy, there
is no pathognomic symptom for idiopathic hypersomnia. Narcolepsy is currently
believed to be due to a deficiency in hypocretin-producing neurons in the lateral
hypothalamus, possibly as a result of an autoimmune disorder. The pathophysiology
of idiopathic hypersomnia is currently unknown. The diagnosis is made by the
presence of appropriate clinical symptoms and confirmation by polysomnography
followed by an MSLT. The MSLT typically shows a short sleep latency (£8 min for
narcolepsy and <8 min for idiopathic hypersomnia) with two or more sleep onset
REM periods in narcolepsy patients vs. less than two sleep onset REM periods in
idiopathic hypersomnia patients. In patients with cataplexy, CSF hypocretin levels
are typically £110 pg/mL, but CSF histamine levels are reduced in both disorders.
There are both nonpharmacologic and symptom directed pharmacologic (e.g., CNS
stimulants, modafinil, sodium oxybate, certain antidepressants) treatments that usu-
ally are used together for optimal management of excessive sleepiness. Pharmacologic
management for the cataplexy of narcolepsy includes medications with prominent
NE reuptake inhibition and sodium oxybate.

Summary of Keypoints

• Narcolepsy is a syndrome consisting of EDS, cataplexy, sleep paralysis, and

hypnagogic hallucinations. Additional features include automatic behaviors
and fragmented or disrupted nighttime sleep.
• Classic narcolepsy symptoms are difficult to identify in children as sleepiness
may manifest as inattentiveness, lack of energy, behavioral problems, or decreased
performance.
16 Narcolepsy and Idiopathic Hypersomnia 311

• Cataplexy is the most specific symptom of narcolepsy consisting of an abrupt,

bilateral loss of skeletal muscle tone, triggered by sudden emotion such as laughter.
Cataplexy is seen in 60–90% of patients with narcolepsy.
• Poor nighttime sleep is also common in narcolepsy, due to a dysfunction of cen-
tral sleep regulation which causes frequent transitions between sleep and wake-
fulness throughout the entire 24-h cycle.
• Most cases of narcolepsy with cataplexy are associated with loss of hypocretin-
containing hypothalamic neurons; cases of narcolepsy without cataplexy may be
caused by a partial loss of these neurons.
• Sleep disturbances, including excessive sleepiness, may occur following TBI. It
is important to consider TBI among the causes of EDS.
• Appropriate sleep hygiene is critically important in patients with narcolepsy or
idiopathic hypersomnia. Short naps (15–20 min) 2–3 times/day can help control
sleepiness in narcolepsy and improve alertness. However, scheduled naps are not
recommended in idiopathic hypersomnia.
• Stimulants are the mainstay of management of daytime sleepiness in patients with
narcolepsy or idiopathic hypersomnia. Most clinical studies of stimulant medica-
tions report objective improvements in sleepiness in 65–85% of subjects.

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Chapter 17
Parasomnias

Hrayr Attarian

Introduction

There appears to be a lot of confusion in the medical community about what constitutes
a parasomnia and how prevalent these conditions are. In the past, any sleep disorder
that was not breathing related or did not present with prominent insomnia or daytime
sleepiness was called a parasomnia. The International Classification of Sleep Disorders
second edition (ICSD 2) restructured the different sleep disorders into pathophysi-
ologically based categories. According to the ICSD 2, parasomnias are undesirable
physical or experiential events that occur in and around sleep. It lists 16 parasomnias
divided into three categories: NREM parasomnias or disorders of arousal, REM
parasomnias, and other parasomnias.

NREM Parasomnias or Disorders of Arousal

Confusional Arousal

Definition

Confusional arousal is a condition of partial or incomplete awakening usually out of

slow wave or stage N3 sleep. The arousal is associated with slow mentation, relative
unresponsiveness to the environment, occasional complex behaviors, and partial or
total amnesia for the event. There is no autonomic hyperactivity as in sleep terrors
and no wandering as in sleepwalking.

H. Attarian (*)
Northwestern University Feinberg School of Medicine, Department of Neurology,
710 N. Lake Shore Drive #524, Chicago, IL 60611, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 315
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_17,
© Springer Science+Business Media, LLC 2012
316 H. Attarian

Clinical Symptomatology

Confusional episodes result from incomplete arousals during the first third of the
major sleep period. They are characterized by complex and inappropriate behaviors,
nonsense vocalizations, and unintelligible utterances. They rarely leave the bed and
they do not exhibit signs of autonomic hyperactivity seen in sleep terrors. There is,
however, potential for violence if the patient is forcibly aroused. External stimuli that
cause sudden awakenings can lead to confusional arousals in the first 2–3 h of sleep.
Events generally last minutes to hours and generally the more the external stimula-
tion the longer they seem to last. There is memory impairment for the event in over
half of subjects with confusional arousals [1]. A variant of confusional arousal
happens with morning awakenings especially in people with primary hypersomnias
or sleep deprivation. This is sometimes called “sleep drunkenness” or in French “Ivresse
du Sommeil” and is characterized by clumsiness and mental cloudiness. Sleep depri-
vation can also lead to confusional arousals out of prolonged daytime naps as well.

Etiology

There are no known etiological factors other than age as it is much more prevalent
in children than adults. There are, however, precipitating factors such as use of
central nervous system (CNS) depressant medications, sleep deprivation, exposure
to alcohol, and certain metabolic conditions that can affect the CNS.

Pathophysiology

Confusional arousals are manifestations of incomplete arousal from N3 sleep.

Impairment in cognitive function and delayed responsiveness occurs in healthy
sleepers as well if they are awakened from slow wave N3 sleep. Electrophysiological
recordings during confusional arousals have demonstrated the coexistence of the
hallmarks of different sleep stages within a single epoch.
There may be arousal in the limbic system with persistence of slow wave activity
in the associative cortical areas responsible for higher cognitive functions [2].

Epidemiology

The prevalence ranges from 2.9% in adults to 17.3% in children without gender
predilection [3].

Diagnostic Workup

Often history or a home video of the event is enough to make the diagnosis but in
atypical cases video EEG monitoring may be required to rule out nocturnal seizures.
Sometimes a PSG with extra EEG leads can be sufficient if an event occurs or one
is precipitated by forced arousal from N3 sleep.
17 Parasomnias 317

Treatment

Reassurance in children with confusional arousals is first-line treatment as they

often “outgrow” them with age [4]. Anticipatory or scheduled awakening is a behav-
ioral technique used to prevent confusional arousals. Because the occurrence of
these events is very often time-locked to the first third of the night awakening of
the child, 15–20 min prior to the usual time of occurrence may alter the sleep state
and therefore abort the event. During the scheduled awakening, the parent should
comfort the child [3]. When confusional arousals become frequent and intractable
the possibility of comorbid sleep disordered breathing or, to a lesser extent, sleep-
related movement disorder should be explored. Treating these underlying conditions
often eliminates the confusional arousal [5].
During a confusional arousal, efforts to curtail the behavior may lead to aggression
because of the physical proximity and provocation and therefore should be avoided
[6]. The episode should simply be allowed to run itself out, unless there is an attempt
to leave the bed [7]. There is no specific pharmacological management for confu-
sional arousals and often none is needed [7]. Anecdotal evidence suggests, however,
that some tricyclic antidepressants such as imipramine and clomipramine might
benefit some patients as can low dose clonazepam [7]. Patients should avoid any
known precipitating factors, such as sleep deprivation, shift work, or CNS depres-
sants especially alcohol [8].

Sleepwalking or Somnambulism

Definition

Sleepwalking is a disorder of arousal characterized by complex purposeless tasks

and wandering episodes of variable duration, with memory impairment for the
event.

Clinical Symptomatology

Sleepwalking usually occurs in the first 2–3 h of the major sleep period, when N3
sleep is the most prevalent stage. Sleepwalkers perform movements of varying
complexity that range from just changing positions on bed to actually getting out of
bed and walking to cooking, eating, and even driving a car. All movements, how-
ever, are clumsy and purposeless. Even when the event is associated with talking,
speech is slow and poorly reactive. They do though sometimes respond to com-
mands of returning to bed. They may carry on incoherent conversations but they
never scream, yell, or otherwise make any alarming vocalizations or show signs of
autonomic hyperactivity. The onset of the event is usually abrupt and the subjects
are usually indifferent to their environment, have a blank facial expression, and
have little or no awareness of their surroundings. They may react minimally but usually
318 H. Attarian

are unresponsive and difficult to arouse despite the fact that they appear awake
although disoriented and confused. Episodes usually begin abruptly, and patients
show a blank expression, indifferent to the environment with a low level of
awareness and reactivity. Sleepwalking has potential forensic implications because
of rare injurious behaviors including homicides that have occurred [9]. Violence
often occurs when attempts to wake the sleepwalker lead only to partial arousal.
Amnesia for the event is quite common unless the person was fully awakened
during the event. There have been, however, reports of some elaborate dream-
like experiences.

Etiology

Genetics seem to play a big role in sleepwalking as it often runs in families

together with other NREM parasomnias. Sleepwalking occurs with higher con-
cordance in monozygotic than dizygotic twins [10] and there is an association
between sleepwalking and HLA-DQB1*05 subtype [11]. Sleepwalking occurs
commonly in children aged 5–16 years, with a peak at age 10. CNS maturational
factors may play a role in the termination of episodes by late adolescence. Because
of its strong association with migraines but not other types of headaches [12] a
dysfunction of the sertonergic system has also been implicated as a contributing
factor [13]. Adults who present with sleepwalking have often had history of sleep-
walking in childhood or never stopped sleepwalking in late adolescence, although
rare adult onset has been reported. It is very important to recognize in clinical
practice that drugs both prescribed and recreational can cause sleepwalking and
although zolpidem and other sedative hypnotics have been recently implicated
more often than other medications the potential exists with any CNS active agents.
Even though sleepwalking tends to be more prevalent with psychosocial stressors,
contrary to popular lore, sleepwalking in adulthood is not a sign of psychiatric
illness [14].

Pathophysiology

As with the other NREM parasomnias, sleepwalking tends to arise most of the time
from stage N3 sleep, but may occasionally arise out of N2 sleep. Although no direct
evidence exists the current thinking based on robust circumstantial date is that
sleepwalking is due to an arousing stimulus leading to incomplete cortical activa-
tion. Sleepwalkers tend to have NREM sleep instability with inability to maintain
consolidated N3 sleep [15]. Single Photon Emission Computerized Tomography
(SPECT) studies in sleepwalkers have shown activation of the thalamocingulate
tracks (responsible for motor activity) with continued quiescence of thalamocortical
tracks (responsible for wakefulness). Therefore, during sleepwalking the mind is
sleep while the motor systems are awake [16].
17 Parasomnias 319

Epidemiology

Prevalence of sleepwalking varies from 4% in adults to 17% in children under the

age of 13 [17].

Diagnostic Workup

In most typical cases, history alone is sufficient to make a diagnosis but in atypical
presentations, especially in adults, nocturnal seizures need to be ruled out that is
why a couple of nights of video EEG monitoring is usually sufficient to make a
diagnosis [18]. If other underlying sleep disorders are suspected then a PSG with
additional EEG electrodes may be helpful [19]. In addition, sleep depriving the
patient the night before may increase the yield of capturing an event during the PSG
[20, 21].

Treatment

Because of absence of randomized trial data on the efficacy of pharmacological

measures the first-line treatment for sleep walking is supportive. This includes
avoiding sleep deprivation and treating other apparent predisposing factors (e.g.,
sleep disorders), addressing triggering factors (e.g., environmental stresses and
intake of alcohol and other drugs) and creating a safe environment for the sleep-
walker (removing objects they can bump into, locking windows, etc.), quietly
guiding him or her back to bed if necessary and reassuring that underlying
psychiatric illness is not the cause of the sleepwalking [22]. With pediatric cases
parents should also be reassured, once other conditions such as seizure disorders,
have been ruled out, that most affected children usually outgrow the condition by
late adolescence, or sooner [3]. In addition, anticipatory or scheduled awakening,
described earlier, can also be utilized to prevent sleepwalking [23, 24]. Other
nonpharmacological methods of treatment include psychotherapy and stress
management [7], including hypnosis [25] (see Table 17.1 for a detailed list). The
evidence for these methods is only based on anecdotal data and case reports and the
only randomized, blind trial (only 11 participants) that compared active hypnosis to
suggestion hypnotherapy with crossover did not show any additional benefit with
the active therapy [26].
If the sleepwalking is putting the patient and the family at risk for injury or if the
events are frequent and disruptive to both families’ and patients’ sleep then pharma-
cological management is recommended.
Several case reports and anecdotal data have shown that patients respond to
benzodiazepines such as diazepam 2–5 mg [25] although in a small (five subjects)
double blind crossover study, the only one of its kind, diazepam was not superior to
placebo because all five patients significantly improved [27]. Clonazepam at 0.5–2 mg
is the best documented medication for sleepwalking in several case series [28, 29].
320 H. Attarian

Table 17.1 Summary of therapies for NREM parasomnias

Parasomnia Nonpharmacological treatment Pharmacological treatment
Confusional Scheduled awakening Imipramine/clomipramine
arousals Clonazepam
Sleepwalking Scheduled awakening Diazepam (although small randomized trial
did not show benefit)
Stress management Clonazepam/ Triazolam/flurazepam
hypnosis (although small Imipramine
randomized trial did Melatonin
not show benefit) Paroxetine
Sleep terrors Scheduled awakening Trazodone
hypnosis Paroxetine
Relaxation therapy Diazepam/clonazepam
Hydroxytryptophan
Imipramine/clomipramine

Other benzodiazepines that have been shown effective include triazolam 0.25 mg at
bedtime [30] and flurazepam [31]. Imipramine 20–100 mg at bedtime is effective
for many patients [25, 32, 33]. Lastly, paroxetine is reported effective in isolated
cases [34, 35]. When patients with initially frequent sleepwalking are totally con-
trolled for 4–6 months, nightly use of medication should be followed by gradual
withdrawal within a year, and resumption if symptoms return [25].
Some case studies have suggested that melatonin therapy, at 5 mg, half an hour
before bedtime, may be helpful for patients with sleep walking [36].

Sleep Terror or Pavor Nocturnus

Definition

Sleep terror is a NREM parasomnia characterized by an explosive onset, autonomic

hyperactivity, and a “blood curdling” scream.

Clinical Symptomatology

Sleep terrors usually consist of an abrupt arousal from stage N3 sleep with a sudden
scream and incoherent verbalizations often within the first hour of the major sleep
period. The individual then enters a state characterized by autonomic hyperactivity
[4] and behavioral manifestations of intense fear and sometimes an apparent desire
to escape. Episodes are usually short lasting under 5 min except on rare occasions
can be as long as 20 min, and not occurring more than once a night. Patients do not
usually leave the bed although jumping out of bed and running through the house
have been reported. Patients quickly return to sleep and there is usually amnesia for
17 Parasomnias 321

the event the next day or the recollection is limited to a single frightening image or
situation. In rare, severe cases, injury to the patient or people trying to restrain him
or her may occur.

Etiology

As with sleepwalking, genetic factors play a role in the etiology of sleep terrors with
increased prevalence among subjects with family history of sleep terror or any of
the other two NREM parasomnias. Twin studies also support the role of genetics
[37]. Sleep terrors have also been reported in posttraumatic stress disorder (PTSD)
[38], in children with OSA [5], and patients with certain brain lesions [39].

Pathophysiology

The exact pathogenesis remains unknown but as with all disorders of arousal sleep
terrors tend to rise out of N3 sleep and disorder of arousal mechanisms with frag-
mented N3 sleep has been implicated as one causative factor [40, 41].

Epidemiology

Prevalence of sleep terror also varies with age from 1% in the elderly to 6.5% in
children [8].

Diagnostic Workup

History alone is usually sufficient to make the diagnosis of typical sleep terrors but
as with other parasomnias nocturnal seizures need to be ruled out with video EEG
monitoring in atypical presentations and if other sleep disorders such as OSA is
suspected a PSG also is recommended.

Treatment

Reassurance is often enough in young children with infrequent spells of sleep

terrors because they tend to outgrow it by late adolescence [4]. It is, however, very
important to have safety measures in place to avoid injury [4]. Any attempt at inter-
rupting the episode is discouraged because it will frighten the person experiencing
the sleep terror and may lead to violence [42]. It is preferable to wait until the spell
is over and then guide the person gently back to bed [42].
The bedroom environment should be made as safe as possible to minimize the
risk of injury. These include locating the patient’s bedroom on the ground floor,
322 H. Attarian

providing special bolts for windows and doors, removing obstructions in the
bedroom, and installing alarms on outside doors [42]. In children, anticipatory or
scheduled awakening, described earlier, can also be utilized to prevent sleep terrors
[23, 24].
The patient should be counseled to avoid sleep deprivation and other precipi-
tants, such as drugs and alcohol [7]. Attempts should be made to alleviate whatever
stress may be going on in the patient’s environment and to ensure that the patient
(especially a child) is getting adequate rest [43].
If the behaviors are dangerous to person or property or extremely disruptive
to family members then there are both behavioral and pharmacological methods to
treat sleep terrors [7].
Behavioral methods include psychotherapy [44], relaxation therapy [45], and
autogenic training or hypnosis [46].
Pharmacological interventions include benzodiazepines such as diazepam
5–10 mg [47] or clonazepam 0.5–2 mg [29] and tricyclics such as imipramine [48]
or clomipramine [49] may be beneficial. Other medications that have anecdotal
evidence for their efficacy are trazodone and paroxetine [50 ] , melatonin 5 mg
in children with pervasive developmental disorders [36, 51], and lastly l-5-hy-
droxytryptophan, a precursor of serotonin, (2 mg/Kg at bedtime) has been proposed
as highly effective in reducing the number of sleep terror episodes [52].

REM Parasomnias

REM Sleep Behavior Disorder

Definition

Sleep behavior disorder (RBD) is characterized by the absence of atonia in REM

sleep resulting in dream enacting behavior that can lead to injury to self and
bed partner.

Clinical Symptomatology

The most common presenting symptom is the violent and dramatic activity in sleep
that can potentially lead to injury. This activity can take the form of loud vocaliza-
tions like talking, yelling, or swearing, and it can cause the patient to grab, jump,
punch, and kick and even run out of bed. Rarely elaborate nonviolent behaviors
can also occur, especially among adolescents and women [53]. Obviously injuries
can be quite common and range from bruises to multiple fractures and can involve
both the person and their bed partner. The violent behaviors and dream content
associated with RBD are usually completely out of character for the patient and
there is no increased daytime aggressiveness [54–56]. There is always memory for
17 Parasomnias 323

the event, which tends to be short with no confusion upon awakening and clear
dream mentation. Events tend to happen in the middle or latter third of the night and
rarely arise out of naps. They can occur anywhere from several a night to one every
few weeks and the patients may have had a prodrome lasting for several years of
frequent sleep talking, periodic limb movements, and tooth grinding.

Etiology

Acute and transient RBD can develop in response to medications especially SSRIs
[57, 58]. A clear etiology of chronic RBD has not been discovered but a clear asso-
ciation between RBD and degenerative neurological illnesses such as synucleinopa-
thies (Parkinson disease, dementia with Lewy Body disease, and multisystem
atrophy) has been clearly established. Often the RBD precedes the other symptoms
of the neurological illness by up to five decades [59]. Another condition closely
associated with RBD is narcolepsy; over 50% of patients with narcolepsy complain
of dream enacting behavior [60].

Pathophysiology

The most likely pathophysiology of RBD is a dysfunction in dopaminergic systems,

particularly in the striatum, but also involving the pons and portions of the frontal
lobe. The evidence for this comes mainly from functional neuroimaging [61–64].

Epidemiology

The estimated prevalence is 0.38% in the general population and 0.5% in elderly
men [65]. RBD is most common in men older than 50 but it may start at any age.
Women, younger adults, and children can also present with it [53, 66–69]. Serum
sex hormone abnormalities do not account for the male predominance [70].

Diagnostic Workup

History of dream enacting behavior and PSG evidence of excessive chin EMG tone
seen on a single night of recording is sufficient to establish the diagnosis even if the
person does not have one of their episodes in the lab [71].

Treatment

RBD-like symptoms can occur in untreated Obstructive Sleep Apnea Syndrome

(OSAS) and treating the underlying sleep-related breathing disorder will generally
324 H. Attarian

control the RBD [72, 73]. Certain antidepressants (SSRIs, venlafaxine, and related
medications) can also precipitate RBD and generally treatment involves stopping
the offending medications [57, 58].
Under all other circumstances RBD must be treated with medications. Creating
a safe environment might help prevent injury but is not a stand-alone treatment.
Although no randomized double blind trials exist [74] two agents shown to be definitely
beneficial are clonazepam and melatonin.
Over 22 published papers and a total of 339 patients, clonazepam, at doses of
0.5–2 mg, taken 30 min before bed, was shown effective in controlling RBD symp-
toms completely in 251 (74%) and partially in 57 (17%) [75]. In addition, clonaze-
pam has been known to normalize chin EMG activity on PSG in some patients with
RBD [76]. Clonazepam should be used with caution in patients with dementia, gait
disorders, or OSA [75].
Melatonin at doses of 3–12 mg (over 6 studies and 31 out of 38 subjects responding)
has also been known to significantly improve but not necessarily completely resolve
symptoms of RBD. It also has the added advantage of a favorable side effect profile
[75]. A recent case report of a patient with the parasomnia overlap variant described
complete resolution of RBD and sleep walking with melatonin but not with clonaze-
pam [77]. No data is available on their combined use.
There are also a host of medications that have shown questionable benefit in
RBD (see Table 17.2 for a detailed list). These include donepezil at 10–15 mg
dose; rivastigmine 9–12 mg; pramipexole at 0.5–1.5 mg; levodopa at variable dosing;
paroxetine at 10–40 mg; zopiclone 3.75–7.5 mg; temazepam, triazolam, and
alprazolam at variable doses; the herbal supplement Yi-Gan San at 7.5 mg; sodium
oxybate and clozapine at unknown doses; low dose desipramine (50 mg); and
carbamazepine 300–1,500 mg a day [75]. Donepezil, 10–15 mg, has shown improve-
ment in a small case series of idiopathic RBD patients [78] but failed to show
significant improvement in RBD patients comorbid with neurodegenerative condi-
tions [79, 80]. Rivastigmine, 9–12 mg, has only been studied in patients with RBD
and Lewy Body Dementia and has shown modest if any benefit [81, 82]. Pramipexole
0.5–1.5 mg has shown to be somewhat beneficial in idiopathic RBD [83] but
not RBD with parkinsonian syndromes [84] and levodopa at 100 mg, in patients
with parkinsonism has improved but not resolved RBD symptoms [85]. Despite the
ample data available on the negative effect of SSRIs on RBD there is a single case
report where paroxetine [86] improved both clinical symptoms and PSG signs of
idiopathic RBD.
Therefore, the AASM standards of practice committee recommend the following:
Pramipexole may be considered to treat RBD but efficacy studies have shown contradictory
results. There is little evidence to support the use of paroxetine or l-DOPA to treat RBD,
and some studies have suggested that these drugs may actually induce or exacerbate RBD.
There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they
may be considered to treat RBD in patients with a concomitant synucleinopathy [7].

The other medications listed earlier may be used for RBD but the data is only a few
case reports, therefore evidence to support their use is very limited [75].
17 Parasomnias 325

Table 17.2 Summary of therapies for REM parasomnias

Nonpharmacological
Parasomnia treatment Pharmacological treatment
RBD none Melatonin: Level B evidence
Clonazepam: Level B evidence
Zopiclone, benzodiazepines other than
clonazepam, Yi-Gan San, desipra-
mine, clozapine, carbamazepine, and
sodium oxybate: Level C evidence
Rivastigmine and donepezil Level C
evidence only in the setting of
synucleinopathies
Pramipexole, levodopa, and paroxitine
(controversial evidence)
Parasomnia Overlap Clonazepam: Level B evidence
Syndrome
Isolated Sleep none Tricyclic antidepressants: Level B
Paralysis evidence
SSRIs: Level C evidence
Magnetic stimulation (one case report)
Nightmares Image Rehearsal Prazosin: Level A evidence (only in
Therapy: Level PTSD)
A evidence
Systematic Desensitization Tricyclic antidepressants, phenelzine,
and progressive deep fluvoxamine, trazodone, olanzapine,
muscle Relaxation: topiramate, gabapentin, cannabinoid,
Level B evidence low dose cortisol, cyproheptadine
triazolam and nitrazepam: Level C
Exposure, relaxation, and Clonidine: Level C evidence (only in
rescripting therapy PTSD)
(ERRT); sleep dynamic
therapy; hypnosis;
eye-movement desensiti-
zation and reprocessing
(EMDR); and the
Testimony Method:
Level C

Parasomnia Overlap Syndrome/Status Dissociates

These are two subtypes of RBD with an unknown prevalence and tend to occur in
a variety of neurological and psychiatric conditions. The first is characterized by
the co-occurrence of both RBD and a NREM parasomnia usually sleep walking or
confusional arousal and the latter is characterized by the complete breakdown of
all interstate boundaries resulting in no identifiable sleep/wake stages [87 ] .
For all practical purposes, their diagnostic workup and treatment is the same as
that of RBD.
326 H. Attarian

Isolated Recurrent Sleep Paralysis

Definition

This is a condition characterized by a pathological dissociation between level of

alertness and the generalized muscle atonia typical of REM sleep leading to the
feeling of being paralyzed but entirely alert [88].

Clinical Symptomatology

Isolated paralysis most often occurs when awakening (postdormital or hypnopompic

type) whereas the familial and the type associated with narcolepsy tend to occur
more while falling asleep (predormital or hypnagogic) [89]. Both types, however,
can occur in all three conditions.
The person is unable to move limbs, facial muscles, or vocalize. Although there is
a subjective sense of shortness of breath, respiratory muscles are spared. The person
experiencing it is always fully awake and can easily recall the event afterwards. The
episode lasts seconds to minutes (average duration 4 min) and usually resolves
spontaneously but may be aborted by sensory, usually tactile, stimulation [89]. Intense
anxiety is often a feature of the event and hallucinations can accompany sleep paralysis
up to ¾ of the time. Relapses can occur especially if one is lying in the supine position.
Frequency of the episodes is also more in supine sleepers and those who experience it
at the beginning and middle of the night rather than at the end of the night. Timing also
affects severity of the anxiety with sleep onset episodes being more anxiety provoking.
Usually sleep paralysis leaves no sequelae but on rare occasions, some weakness or
numbness in the extremities may persist for a few minutes [90].

Etiology

The etiology of isolated recurrent sleep paralysis is unknown.

Pathophysiology

A dissociated state of mixed wake and REM sleep is the most likely cause of
sleep paralysis [91]. This is most likely due to hyperactivity of the cholinergic sys-
tems in the brainstem as well as hypoactivity of the noradrenergic and serotonergic
mechanisms.

Epidemiology

The prevalence varied between 5 and 40% depending on frequency of the experience,
age group, and type of questionnaires used [92–97].
17 Parasomnias 327

Diagnostic Workup

Polysomnography captures sleep onset REM periods and dissociated states of wake
and REM if the events are frequent enough to be captured during a recording [98].
History alone may also be sufficient but the recently developed Unusual Sleep
Experiences Questionnaire can also be of use [99].

Treatment

Sleep deprivation can increase the frequency of sleep paralysis and can often
precipitate an episode. Avoidance of sleep deprivation is highly recommended espe-
cially in cases of shift work and other related circadian problems such as jet lab,
irregular sleep habits, etc [100]. In cases of isolated or familial sleep paralysis or
with narcolepsy when episodes are quite frequent then pharmacological interven-
tion is warranted. Medications that have shown to be effective by anecdotal reports
include clomipramine 25–50 mg at bedtime; [101] imipramine at a dose of 25–50 mg
[102]; protriptyline 2 –10 mg; fluoxetine 10–30 mg; viloxazine 25–50 mg; and
femoxetine 100–150 mg [103]. Their proposed mechanism of action is through
REM suppression [104]. A single case report of a patient with multiple sclerosis
and frequent isolated sleep paralysis describes resolution of the paralysis with
extracerebral weak electromagnetic field [105].

Nightmares

Definition

Nightmares are anxiety and fear provoking recurrent dreams.

Clinical Symptomatology

The four cardinal criteria to diagnose nightmares are:

1. A sudden awakening from sleep with intense fear, anxiety, and a feeling of
impending harm.
2. Immediate recall of frightening dream content.
3. Full alertness on awakening with little confusion or disorientation.
4. A delayed return to sleep, or the episode occurs in the last half of the night [88].
There usually is a lack of shortness of breath, autonomic hyperactivity, or motor
behaviors.
328 H. Attarian

Etiology

Two theories of nightmare etiology exist. The first, and the more valid one, postulates
that nightmares are simulations of threatening events and serve a rehearsal function
important for survival [106]. The second, which requires further testing to prove its
validity, states that nightmares reflect negative waking-life experiences [107].
A number of medical conditions are also associated with nightmares and these
include: advanced cancer [108], hypoglycemia resulting from insulin treatment
[109], psychiatric disorders [110] especially PTSD [111], drugs (propranolol,
levodopa, mementine, donepezil, valsartan, fluoxetine, reserpine and withdrawal
from alcohol, barbiturates and high dose tricyclic antidepressants) [112–115], OSA
[116], Parkinson disease [117], and epilepsy [118].

Pathophysiology

Pathophysiology of nightmares is poorly understood but it is most likely a combina-

tion of genetic and environmental factors.

Epidemiology

The prevalence, depending on age, comorbid conditions, and frequency of occur-

rence, varies from 2 to 85% [119].

Diagnostic Workup

History alone is usually sufficient to establish the diagnosis. Comorbid conditions

may need to be ruled out.

Treatment

Nonpharmacological methods of treatment verified by small randomized trials

include cognitive behavioral therapy [120] specifically imagery rehearsal therapy a
technique where subjects change the endings of their nightmares, while they are
awake, by rehearsing the new, nonthreatening images associated with the changed
dream [121], cognitive restructuring called “lucid dreaming treatment,” where the
subject is taught to realize that they are dreaming and change the content of their
nightmares [122] self-exposure therapy (controlled exposure to cues associated
with the nightmares; a form of desensitization) [123] and hypnosis [124]. A combi-
nation of sleep hygiene and a few of the above mentioned techniques showed
improvement in both the psychiatric symptoms and sleep disturbances in an open
label trial with PTSD patients [125] as did a combination of dream rehearsal, lucid
17 Parasomnias 329

dreaming, and relaxation techniques [126]. Another randomized, clinical trial of

cognitive-behavioral treatment for chronic nightmares in adults also reported a
significant decrease in the nightmares themselves and significant improvement of
comorbid depression, PTSD, quality and quantity of sleep. Using cognitive-
behavioral treatment as a first-line therapy for trauma-exposed individuals with
chronic nightmares is supported by this and other studies [127].
The best studied and most effective pharmacological measure to treat nightmares
with PTSD has been the centrally active alpha1-adrenergic antagonist prazosin at
1–4 mg a day. Several trials both open label and placebo controlled have shown sig-
nificant improvement in nightmares and associated sleep disturbances [128–133].
One of the mainstays of pharmacological treatment in most parasomnias,
clonazepam, has been shown ineffective in controlling nightmares and related sleep
disturbances in PTSD patients [134] but two other benzodiazepines, 0.5 mg
triazolam and 5 mg nitrazepam, have anecdotal evidence of efficacy [135]. No data
is available as to its efficacy in non-PTSD chronic nightmare sufferers. Other
medications that have shown some benefit include the antidepressants nefazodone
(not to be used first line because of hepatotoxicity [135]) with dosages of 400–
600 mg [136] and trazodone 50–200 mg [137]. Both appear effective for the treat-
ment nightmares and associated insomnia in noncontrolled open label trials. Other
antidepressants with anecdotal evidence supporting their efficacy in nightmares
include phenelzine, fluvoxamine, imipramine, doxepin, and amitryptiline [135].
Other medications that have been used in open label trials and have been shown
somewhat effective include clonidine 0.2–0.6 mg in divided doses [135], cypro-
heptadine 16–24 mg per night, and 10 mg per day of cortisol [135]. Two anticonvul-
sants also have shown significant improvement in the frequency of nightmares and
associated sleep disturbances in open label trials. These are gabapentin 300–
3,600 mg per day [138], and topiramate at 75 mg a day [139], so has the atypical
antipsychotic olanzapine at 10–20 mg a day doses [140]. Most recently a synthetic
cannabinoid has shown significant improvements in number and frequency of night-
mares in an open label trial [141].

Other Parasomnias

Sleep-Related Dissociative Disorder

Sleep-related dissociative disorder is a relatively new parasomnia that appeared in

2005 in the ICSD-2. It is the nocturnal variant of the psychiatric conditions that are
grouped together under dissociative disorders [88].
Very little is known about its etiology or pathogenesis except that most if not all
patients who experience sleep-related dissociative disorder have history of exten-
sive sexual or physical abuse very often beginning in childhood [142]. Although the
clinical criteria and symptomatology are the same as that of daytime dissociative
330 H. Attarian

disorders criteria include the diagnosis of a dissociative disorder based on DSM-IV-TR

criteria, dissociative episodes can exclusively or primarily arise from the main
sleep period [143].
Clinically dissociative episodes occur when the person is technically awake by
EEG criteria. The timing is usually either while transitioning from wake to sleep or
during awakenings out of the major sleep period [29].
Diagnosis is made using the same DSM IV TR criteria as dissociative disorders
which are characterized by disruptions of aspects of consciousness, identity, memory,
motor behavior, or environmental awareness [144]. When events are captured during
a PSG preferably with a full head EEG montage the subject is usually awake by
EEG criteria but are completely unaware of their own actions and surrounding but
the behaviors can be so complex as to lead to injury to self or others. It is unclear
whether the sleep-related dissociative disorder represents a different clinical entity
or if it is a subtype of the dissociative disorders in general [144]. The prevalence is
unknown and the only epidemiological study reported that 5.3% of a sample of 150
patients with sleep-related injury had sleep-related dissociative disorder [143].

Treatment

Various forms of psychotherapy are the mainstay of treatment for this challenging
disorder. The involvement of a highly trained psychotherapist is key to successful
treatment. Cognitive-behavioral therapy, sensorimotor psychotherapy (a method
that integrates sensorimotor processing with cognitive and emotional processing
in the treatment of trauma) [145], posttraumatic disorder treatment, and clinical
hypnosis are all known to help [146]. Expressive artwork and journal entries can be
useful complements to therapy and safety planning is essential because of high risk
of suicidal ideation with patients with dissociative disorders [4].

Sleep Enuresis

Definition

Sleep enuresis is defined as sleep-related recurrent and involuntary urination or in

laymen terms bedwetting.

Clinical Symptomatology

Enuresis is categorized as monosymptomatic or nonmonosymptomatic and also as

primary or secondary.
When enuresis occurs in the absence of any daytime urinary symptoms then it is
classified as monosymptomatic. The nonmonosymptomatic type is more common
17 Parasomnias 331

as the majority of children have enuresis also exhibit subtle daytime symptoms.
Secondary enuresis is bedwetting that develops after at least 6 consecutive months
of dryness. The clinical presentation of primary and secondary enuresis is otherwise
similar [147].

Etiology

The etiology of enuresis remains unknown. Risk factors and contributors include
CNS immaturity, disorders of arousal, increased fluid intake, urinary problems both
functional and structural, male gender, maternal smoking, mother’s age less than 20
at the time of the child’s birth, psychosocial stressors, and ADHD [148, 149].

Pathophysiology

The pathogenesis of enuresis remains unknown but genetics plays a major role in its
development as enuresis is more common in children born to enuretic parents than
in the general population. The incidence is 77% when both parents were enuretic
and 44% when one parent was enuretic. In addition, 70% of enuretic children have
at least one other sibling who also wets the bed. The inheritance pattern appears to
be autosomal dominant with markers on chromosomes 12, 13, and 22 [150].
Psychosocial stressors, medications, and CHF (in the elderly) play a role in enuresis
[151] as well in addition to hormonal changes such as lack of the normal nighttime
peak in antidiuretic hormone [152] and elevated mean arterial pressure [153].

Epidemiology

Approximately, 4% of 8 year olds have enuresis twice a week, 80% of 2 year olds,
30% of 4 year olds, 18% of 5 year olds, 10% of 6 year olds, 8% of 8 year olds, 3–4%
of 12 year olds, and 1% of 15 year olds have enuresis at least once a month [154–156]
and 8% of 7–15 year olds bedwet at least once every 3 months [157]. A total of
75–80% of cases are primary and 20–25% are secondary. The primary to secondary
ratio decreases with increasing age, with each type accounting for half the cases
by early adolescence. The female to male ratio in preadolescents is 1/1.5.

Diagnostic Workup

Should include comprehensive sleep and urological history, a careful physical exam
and urinalysis. Ultrasonography, vesical sphincter electromyography, cystometry,
and cystoscopy may be useful for some children who have daytime symptoms or are
resistant to treatment. A PSG with or without extra EEG channels may be indicated
if OSA or nocturnal epilepsy is suspected [147]
332 H. Attarian

Treatment

The treatment of sleep enuresis should start by ruling out, with a careful history and
examination, and treating potential secondary causes of it. OSAS is a known cause
of bedwetting [158] as are genitourinary and renal problems [159], seizures [160],
Attention Deficit Disorder (ADD) [161], diabetes mellitus [162], certain medica-
tions (certain antipsychotics, valproate, selective serotonin reuptake inhibitors
(SSRI) [163–166], hyperthyroidism [167], and psychological factors such as history
of sexual abuse [168]. When the above have been ruled out then the treatments of
enuresis fall under three major categories: behavioral therapy, alarm therapy (used
primarily in children), and pharmacotherapy [147]. Behavioral therapy is supported
by a wealth of clinical and anecdotal data but no randomized trials are available to
validate its efficacy. Nevertheless, it has very few drawbacks and should be attempted
as first line. It includes proper bowel regimen to avoid hard stools or constipation as
this may cause of worsen enuresis [169], increasing fluid intake during the morning
and early afternoon hours and limiting it during the evening and night time [170],
encouraging the patient to avoid holding urine and to void at least once every 2 h
[147, 170], and biofeedback to help relax the pelvic floor muscles [147, 171]. Alarm
therapy has been shown to be efficacious in multiple randomized trials [172].
It involves using a moisture sensitive alarm that goes off and awakens the child at
the moment of bed wetting. It improves the child’s ability to wake up from sleep by
using classical conditioning or avoidance conditioning [173]. In successful cases,
enuresis is replaced by nocturia [174]. Response is seen in the first month and treat-
ment is continued for up to 6 months. If there is no response during the first month
then the therapy is considered a failure and is discontinued [147]. Pharmacological
treatments do not constitute a cure and generally relapses occur once the patient
has stopped the medication. The drugs that have randomized trial support for
efficacy include anticholinergics (especially antimuscarinic agents), e.g., oxybu-
tynin, DDAVP or desmopressin, tricyclic antidepressants for children [147] and for
adults all the above plus verapamil (55% efficacy and well tolerated) [175] (see
Table 17.3 for a detailed list). There are anecdotal reports of acupuncture [176],
spinal blocks with opiates [177], and bladder transection surgery [178] being help-
ful in adults with enuresis but most of these reports are from 20 or more years ago.
Desmopressin is used as first-line pharmacotherapy for children with enuresis at
200–600 mg tablets 1 h before bedtime. Its mechanism of action appears to be the
reduction of nocturnal polyuria [147] It has up to 48% efficacy [179–181] but has
the risk of water intoxication that can lead to coma and seizures due to hypona-
tremia [182]. This is especially true with the nasal spray formulation, therefore the
nasal spray is not recommended in children [183]. Postmarketing case report and
Medline survey from 1972 to 2005 conducted by Robson and colleagues identified
151 cases of hyponatremia with desmopressin out of which 145 were with the nasal
spray and only 6 with oral tablets [183]. Caution is also advised while adding this
medication to others that may potentially reduce seizure threshold or worsen
hyponatremia [183]. Both desmopressin nasal spray and tablets have been shown
effective with a is recommended for adults with enuresis with a 31–54% efficacy
17 Parasomnias 333

Table 17.3 Summary of therapies for other parasomnias

Parasomnia Nonpharmacological treatment Pharmacological treatment
Sleep related Cognitive-behavioral therapy None
dissociative
disorder
Sleep enuresis Behavior modifications DDAVP (controlled trials)
(controlled trials)
Biofeedback (controlled trials) Oxybutynin and tolterodine
(controlled trials)
Conditioning (controlled trials) Tricyclic antidepressants (controlled
trials)
Alarm therapy (controlled trials) Verapamil (controlled trials)
Acupuncture (case report)
Spinal block (case report)
Bladder transection (case report)
Catathrenia CPAP None
Exploding head None Nifedipine (some anecdotal data)
Syndrome Clomipramine (some anecdotal data)
Topiramate (one case report)
Flunarizine (some anecdotal data)
Sleep-related None None
hallucinations
SRED None Pramipexole (small controlled trial)
Topiramate (controlled trial)

and side effects profile that was comparable with both formulations. Symptomatic
hyponatremia was about 5% [184].
There are no monotherapy trials to look at the efficacy of anticholinergics in
pediatric enuresis but there are two recent well-controlled trials of long-acting anti-
cholinergics (oxybutynin 5 mg and tolterodine LA 2 mg) added to desmopressin in
children who did not respond to desmopressin alone. The efficacy was 66–68% and
the combination was well tolerated [185, 186]. Side effects include facial flushing,
heat intolerance, constipation, dry mouth, blurred vision, and increased residual
urine [147]. In adults, oxybutynin at 5 mg doses has been shown effective (70%)
[175] and well tolerated as has tolterodine at 4 mg doses with 69% efficacy [187].
The mechanism of action of anticholinergics is reduction of detrusor overactivity
and an increase in bladder capacity [147].
Third-line pharmacotherapy includes the tricyclic antidepressants whose mecha-
nism of action in enuresis is unknown. There is, however, ample evidence for their
efficacy [147]. In children they are third line primarily because of potential cardiac
toxicity [188]. Imipramine, trimipramine, and other similar antidepressants have
been found effective in 20% of study subjects [188]. The recommended dose usu-
ally is 25–75 mg of imipramine (or the equivalent dose in other antidepressants) at
bedtime [147]. A novel noradrenaline-reuptake inhibitor, Reboxetine, although
pharmacologically related to imipramine, does not have the same risk of cardiotoxicity
334 H. Attarian

and is shown, in one small study, to control enuresis in 32% of study subjects as
monotherapy and for an additional 27% when combined with desmopressin [189].
There are no randomized trials in adults looking at tricyclics for enuresis.
Imipramine at 1 mg/kg dose at bedtime has the best anecdotal data supporting its
use [190, 191]. There are case reports on amitriptyline [192] and maprotiline [193]
being helpful in adults with enuresis as well.

Sleep-Related Eating Disorder

Definition

Sleep-related eating disorder (SRED) is a parasomnia that is characterized by par-

tial arousals from sleep followed by eating or drinking with poor or no memory of
the event afterwards. [194]

Etiology

The etiology of SRED remains unknown but there are a few contributing factors. A
large proportion of SRED patients have some psychopathology, therefore depres-
sion has been proposed as a risk factor [195] but a large Japanese study with a
cohort of 2,023 found no relationship between depression and SRED [196].
Hormonal changes, particularly in melatonin, leptin, and cortisol levels have also
been described in SRED [197] especially in those with insomnia. Finally, SRED has
been seen as a side effect of zolpidem ingestion especially at doses higher than
10 mg [198].

Pathophysiology

Although the exact pathogenesis of SRED is unknown it can be thought of as a

circadian rhythm disorder because of disturbance of the circadian control of eating
in relation to timing of sleep [195]. Some researchers, however, have suggested that
SRED shares a common pathophysiology with arousal disorders because overall
sleep disorders are more common in patients with SRED [199]. Because of an associa-
tion between the restless legs syndrome (RLS) and SRED, a common abnormality in
dopaminergic metabolism has also been implicated in its pathophysiology [200].

Clinical Symptomatology

Patients who suffer from SRED often eat high calorie foods that include elaborate
preparation which, nevertheless, are careless and lead to unintentional self-inflicted
cuts and burns. The episodes tend to arise out of light NREM sleep but may also
arise out of REM. They tend to consume unusual items like salt sandwiches, cat
17 Parasomnias 335

food, and rarely inedible items like soap. Accidental poisoning can occur in addition
to weight gain due to SRED. Subjects deny any feelings of hunger and the eating is
compulsive. Episodes that last for about 4 min may occur 1–8 times a night [201].
About 90% of patients have complete or near complete amnesia for the event and a
minority have vague dream-like mentations [194].
The events can start abruptly as in exposure to sedatives, in the setting psycho-
social stressors, or with other sleep disorders or more insidiously without a clear
precipitant [198, 202]. The course is progressive and the mean age of onset is 25
with 83% of cases being women [203].

Epidemiology

Very little epidemiological data is available in the literature but the few papers out
there report a prevalence of 1.6% among women [204] another reported the preva-
lence of SRED to be 6% among insomniacs referred to a sleep center [205] and 10%
among obese patients [206]. There is also an odds ratio of 4.9 for the risk of devel-
oping SRED among first-degree relatives [207].

Diagnostic Workup

A careful history and physical exam is important to rule out other sleep disorders
and medication exposure that may precipitate episodes of sleep related eating.
Sometimes a PSG preferably with an extended EEG montage is required. There are
no specific PSG abnormalities seen in SRED but consistently SRED patients have
decreased sleep efficiency by about 66–80% [201] and often there are arousals asso-
ciated with masticatory motor movements [208].

Treatment

Again, as with the previously discussed parasomnias, SRED can be a comorbid with
or secondary to other sleep disorders such as OSAS [209], sleepwalking [194, 210],
and RLS [200] so the treatment of the other primary sleep disorder is often effective
in controlling SRED as well. Sometimes SRED is iatrogenic, induced by zolpidem
[211] or other sedative hypnotic medications such as tricyclic antidepressants,
anticholinergics, lithium, triazolam, olanzapine, and risperidone [212], therefore
stopping the offending drug usually controls the problem. In primary SRED, melatonin
[213] and benzodiazepines appear to be ineffective [212] as do cognitive-behavioral
strategies, hypnotherapy and psychotherapy [213]. Low dose pramipexole was
reported effective in a randomized, double-blind, placebo-controlled trial [214] and
so have SSRIs [215] especially with comorbid depression [203]. The most promising
pharmacological intervention is Topiramate, an antiepileptic drug, given at a dose
range of 100–400 mg at night, not only reduces nighttime eating, it also improves
sleep, and leads to weight loss [96, 216, 217].
336 H. Attarian

Exploding Head Syndrome

Exploding Head Syndrome (EHS) is a rare and a poorly documented parasomnia

that is characterized by a painless loud noise or flash of light at the onset of sleep.
It is thought to be a migranous phenomenon [218] [219].

Treatment

The only information we have come from a few case series. Most recommend only
reassurance [219–222], after ruling out intracranial vascular lesions such as dissec-
tions and aneurysms, as this is a benign phenomenon and most often not frequent
enough to be a bother. If the condition becomes disruptive of the patient’s sleep
then there are anecdotal evidence of efficacy with the tricyclic antidepressant
clomipramine 50 mg at bedtime [223], the calcium channel blockers slow-release
nifedipine, 90 mg a day (especially when accompanied by a headache) [224], topi-
ramate [218] and flunarizine 10 mg daily [225].

Catathrenia

Another recently described and rare parasomnia is catathrenia. It was first reported
as REM sleep-related expiratory groaning [226] and was later described in NREM
sleep as well although not with the same prevalence as in REM described apparently
the same phenomenon as “vocalization during prolonged expiration during REM
sleep,” 4 and, in our description of nocturnal groaning, we proposed the term of
catathrenia (meaning “groaning”) in four cases in which the groaning sounds,
though sometimes present also during NREM [227]. The clinical features are quite
stereotyped in all reported cases: a silent deep inspiration followed by a prolonged
2–20 s expiration with groaning. There is associated bradypnea during catathrenia,
without evidence of respiratory muscular effort or oxyhemoglobin desaturation
[228]. It tends to occur in patients without any evidence of other facial, airway, or
lung disease and recent intrathoracic pressure recordings show no activity in the
diaphragm or the intercostals and normal endoesophageal pressures. During groaning,
there is slowing of the respiratory rate by 66% with disproportionate increase in the
length of expiration. Breathing otherwise is normal in sleep [229]. The proposed
etiology is abnormality in central respiratory center resulting in vestigial, central
respiratory pattern during sleep [229].

Treatment

The only reported treatments for sleep-related groaning have been continuous
positive airway pressure (CPAP) [227, 230–232], adenotonsillectomy, and man-
dibular advancement devices [230] even in patients without comorbid sleep apnea.
17 Parasomnias 337

This has fuelled the controversy as to whether catathrenia is a variant of sleep-related

breathing disorder or a distinct parasomnia. Even CPAP has not been reported to
be universally helpful and most patients without sleep-related breathing disorder
are not likely to use it just for the groaning. The exact mechanism of action of
these modalities in catathrenia is unknown but is theorized to be an expansion
of the upper airway [230]. Pharmacological treatments, such as clonazepam
0.5–2 mg at bedtime, trazodone 50–100 mg at bedtime, paroxetine 20 mg at bed-
time, dosulepine 75 mg at bedtime (a tricyclic antidepressant) [233], gabapentin,
pramipexole, and carbamazepine, have been anecdotally tried but failed to control
this condition [230].

Sleep-Related Hallucinations

Although usually associated with narcolepsy, occasional, brief, dream-like imagery

occurring either after waking (hypnopompic hallucinations) or just before falling
sleep (hypnagogic hallucinations) are common in healthy individuals and generally
self-limiting and benign [234]. These are more likely REM sleep phenomenon when
it intrudes into wakefulness.
A rare variant of this is the parasomnia known as sleep-related hallucinations.
It is characterized by prolonged, vivid, complex, and often visual hallucinations
that occur within the major sleep period; usually preceded by awakenings [235].
The hallucinations are almost always visual, colorful and vivid, and often distorted.
Initially there is little to no insight into their unreality, the images often disappear
when the light is turned on. They only happen after awakening within the major
sleep period and never during the day or the major period of wakefulness. In the
published case series, there was a large female preponderance of about 92%.
Although various etiological factors maybe at play such as exposure to beta blockers,
anxiety, dementia, or macular degeneration, the postulated mechanism behind
their development is the thalamic block of sensory input which may predispose to
hallucination development [235].

Treatment

There is very little information on treatment modalities. Sleep deprivation

[234, 236, 237], smoking [234], and certain medications, such as beta adrenergic
antagonists [235], sedative hypnotics [234, 237], and certain antidepressants [234],
tend to trigger it and often reversing these underlying causes relieve the problem.
Among treatments attempted tricyclic antidepressants (nortriptyline and amitrip-
tyline) [235] have been shown ineffective, benzodiazepines have been rarely [238]
if at all effective [235] and hypnosis and other psychological interventions have not
helped [235]. Because these tend to occur during the night when ambient light is
low or absent a parallel has been drawn between it and Charles Bonnet Syndrome
338 H. Attarian

[239, 240], therefore olanzapine at 5 mg a day, a medication shown to be effective

in the latter [241], has been tried with alas not data on its efficacy because the few
subjects who were started on it were lost to follow up [235].

Future Directions

More randomized large-scale trials are needed to assess the efficacy of different
treatment options used in the management of parasomnias. In addition creating an
international registry where information about successful and unsuccessful trials of
different therapeutic options can be entered. This will allow us more easily to assess
the effectiveness of different therapies in the absence of randomized trials since all
the data will be available in one centralized location rather than random case reports
that may or may not end up in medical literature databases.

Conclusion

Parasomnias are common, often benign but sometimes distressing and occasionally
dangerous neurological sleep disorders that are poorly studied. They fall into three
categories: those arising out of REM sleep, those out of NREM sleep, and a third
group that arises out of both states of being. Most information on their treatment
comes from case series and open label trials. Effective treatments include both
behavioral and pharmacological interventions.

Summary of Keypoints

• Parasomnias are undesirable physical and experiential events occurring in and

around sleep.
• According to the ICSD-2, there are 16 parasomnias divided into three
categories.
• The NREM parasomnias or disorders or arousals are three distinct but closely
related conditions that include confusional arousals, sleep walking, and sleep
terrors.
• The REM parasomias include sleep paralysis, REM sleep behavior disorder, and
the related parasomnia overlap syndrome and nightmares.
• The remaining nine disorders fall under the category of other parasomnias.
• Diagnosis almost always includes polysomnography often with additional EEG
or EMG electrodes.
• In overwhelming majority of conditions (nightmares and RBD being the excep-
tions), treatment is based on anecdotal data and expert opinion.
17 Parasomnias 339

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hallucinations: pathological phenomena? Br J Psychiatry. 1996;169:459–67.
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Chapter 18
Movement Disorders

Nidhi S. Undevia

Keywords Sleep-related movement disorders • Restless legs syndrome • Periodic

limb movement disorder • Sleep-related leg cramps • Sleep-related bruxism • Sleep-
related rhythmic movement disorder

Introduction

Sleep-related movement disorders are conditions that are characterized by simple,

usually stereotyped, movements or by sleep-related monophasic motor phenome-
non, such as leg cramps, that disturb sleep. The Second Edition of the International
Classification of Sleep Disorders (ICSD-2) includes restless legs syndrome (RLS),
periodic limb movement disorder (PLMD), sleep-related leg cramps, sleep-related
bruxism and sleep-related rhythmic movement disorder (RMD) under this heading
(Table 18.1). RLS is classified within this group of disorders due to its close associa-
tion with PLMD. Movement alone is not sufficient for the diagnosis of a sleep-
related movement disorder as a nocturnal sleep disturbance or a complaint of
daytime sleepiness or fatigue is required [1]. Each of these topics will be discussed
in this chapter.

N.S. Undevia (*)

Department of Medicine, Division of Pulmonary and Critical Care Medicine,
Loyola Center for Sleep Disorders, Loyola University Medical Center,
2160 S. First Avenue, Maywood, IL 60153, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 349
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_18,
© Springer Science+Business Media, LLC 2012
350 N.S. Undevia

Table 18.1 Sleep-related movement disorders

Restless legs syndrome
Periodic limb movement disorder
Sleep-related leg cramps
Sleep-related bruxism
Sleep-related rhythmic movement disorder

Restless Legs Syndrome

RLS is a sensorimotor disorder characterized by a distressing urge to move the legs

and sometimes other parts of the body such as the arms. The British physician Sir
Thomas Willis first described RLS in the seventeenth century by these very descrip-
tive words “Wherefore to some, when being abed they betake themselves to sleep,
presently in the arms and legs, leapings and contractions of the tendons, and so great
a restlessness and tossings of their members ensue that the diseased are no more
able to sleep than if they were in a place of the greatest torture” [2]. The first signifi-
cant clinical review was carried out by the Swedish neurologist Karl-Axel Ekbom
in the 1940s who also coined the term “restless legs” [3]. The severity of RLS can
vary from mild with only occasional symptoms to daily severe symptoms that can
have a profound effect on sleep and daytime functioning. The pathophysiology of
RLS is incompletely understood, but probably results from derangements in iron
and dopamine metabolism and has a genetic component [4–6].

Demographics

The prevalence of RLS varies from region to region, in Europe, South and North
America and the Indian subcontinent is estimated to be 4–10% of the adult population,
while in Japan, Korea and China, for example, it is 0.6, 0.9 and 1.6% respectively
[7–9]. In the United States it is believed to affect more than ten million adults. The
2005 National Sleep Foundation Poll reported RLS symptoms in 8% of men and
11% of Women [10]. Women appear to be at increased risk of RLS as are middle
aged or older adults [11]. A population survey study reported that the prevalence of
symptoms of RLS was 3% between the ages of 18 and 29 years, 10% between the
ages of 30 and 79 years and 19% in persons older than 80 years of age [12].

Diagnosis

RLS diagnosis is based on clinical grounds and no laboratory study reliably identi-
fies RLS. It does not require a polysomnogram unless an additional sleep disorder
is thought to be present. The diagnosis of RLS in adults according to the Second
Edition of ICSD-2 requires: (a) The patient reports an urge to move the legs, usually
18 Movement Disorders 351

Table 18.2 Diagnostic criteria for restless legs syndrome (RLS)

Uncomfortable sensation in the legs associated with an urge to move
Symptoms are worse at rest
Symptoms are temporarily relieved by movement
Symptoms are worse or only occur at night
The condition is not better explained by another disorder

accompanied or caused by uncomfortable and unpleasant sensation in the legs.

(b) The urge to move or the unpleasant sensations begin or worsen during periods of
rest or inactivity such as lying or sitting. (c) The urge to move or the unpleasant
sensations are partially or totally relieved by movement, such as walking or stretching,
at least as long as the activity continues. (d) The urge to move or the unpleasant sen-
sations are worse, or only occur, in the evening or night and (e) The condition is not
better explained by another current sleep disorder, medical or neurological disorder,
mental disorder, medication use or substance use disorder (Table 18.2) [1]. Separate
diagnostic criteria have been developed for cognitively impaired adults and young
children (age 2–12 years) who have difficulty in reporting these symptoms.

Associated Features

There are several supportive clinical features which, while not required, may assist
in diagnosis. These include a response to dopaminergic agents, periodic leg move-
ments (PLMs) and a positive family history for RLS. PLMs may occur in sleep
(PLMS) and resting wakefulness (PLMW). PLMS occur in 80–90% of patients with
RLS but are not specific for RLS [13]. PLMW may be noted during the wake time
on an overnight polysomnogram. A rate greater than 15 PLMW/h of waking supports
the diagnosis of RLS. The frequency of RLS among first degree relatives of people
with RLS is 3–5 times greater than in people without RLS [14]. There is a negative
impact of RLS symptoms on sleep including reports of disrupted sleep, an inability
to fall asleep and insufficient hours of sleep [11]. Sleep disruption has also been
associated with negative effects on cognitive function in patients with RLS [15].
Onset occurs at all ages from early childhood to late adult life. In children RLS may
be misdiagnosed as “growing pains.” Two age-of-onset phenotypes for RLS have
been described. Early onset RLS usually starts before the age of 45 years with inter-
mittent symptoms and progresses slowly. Late-onset RLS is usually either stable at
onset or rapidly progresses over 5 years to a stable pattern. Patients may describe
the symptoms as creeping, crawling, pulling, aching, prickling or tingling. RLS can
occur unilaterally or bilaterally in the lower extremities. About half (48.7%) of
patients with RLS complain of restlessness in the arms as well. However, every
patient who had arm restlessness also had leg restlessness. In most mild cases or
RLS, symptoms are localized to the lower extremities and only with increased
severity do they also affect the arms and other parts of the body [16]. Peak intensity
of RLS symptoms is on the falling phase of the core temperature cycle suggesting
that RLS is related to the circadian rhythm [17].
352 N.S. Undevia

Differential Diagnosis

The differential diagnosis of RLS includes neuropathic parasthesias, positional

discomfort, akathisia, sleep starts (hypnic jerks), PLM disorder, sleep-related leg
cramps and pain from other conditions. RLS can be distinguished from positional
discomfort as the discomfort is resolved with change of body position without the
need for continued movement and an urge to move the legs is not present. Akathisia
involves a generalized need to move the body and often in association with neuro-
leptic medication. Akathisia sufferers frequently report an inner sense of restless-
ness rather than leg discomfort and lack the circadian pattern characteristic of RLS.
Sleep starts produce brief body movements during the transition from wake to sleep
and an urge to move is not present. PLMD is a disorder that is only present during
sleep without the essential diagnostic features of RLS. Sleep-related leg cramps are
painful sensations caused by sudden and intense involuntary contractions of muscles
and requires strong stretching to relieve symptoms rather than movement alone.
Residual pain is also usually present with sleep-related leg cramps. Pain may be
worse at rest but does not include an urge to move the legs. The presence of pain
does not exclude a diagnosis or RLS as some patients report their RLS symptoms as
pain; however, the additional characteristic features must also be present.

Primary vs. Secondary Factors

RLS can be classified as primary or secondary. The majority of cases of primary

RLS are hereditary (autosomal dominant) with possible loci on chromosomes 12,
14 and 9. Onset of symptoms before the age of 35–45 years indicates an increased
risk of RLS occurrence in the family. Physical and neurologic examinations are
normal in the majority of primary RLS cases [18]. A number of secondary causes
can contribute to RLS and can be expected to improve when the other disorders are
treated. Iron deficiency has been associated with RLS. Pathologic studies suggest
decreased iron and ferritin in the substantia nigra of RLS patients [19]. Low serum
ferritin levels (less than 45 ng/dL) correlate significantly with increased RLS symp-
toms and with decreased sleep efficiency. A significant correlation to serum iron
levels has not been found [20, 21]. Studies suggest disordered transport of iron from
the periphery to the central nervous system [22]. The most commonly reported
neurologic cause of secondary RLS is peripheral neuropathy [18]. Uremia associated
with renal failure has also been identified as a cause of RLS. A 2008 study found
that as many as 58.3% of dialysis patients have RLS [23]. Ekbom made the first
observation that there is a high prevalence of RLS in pregnancy. In a study of 642
pregnant women 26% were found to be affected by RLS during pregnancy. RLS
was strongly associated with the third trimester [24]. A recent study in a French
population of women in their third trimester of pregnancy found that 32% were
affected by RLS. RLS disappeared after delivery in 64.8% of the women [25]. In a
study of 184 narcolepsy with cataplexy patients RLS was found to be significantly
18 Movement Disorders 353

more prevalent compared to controls (14.7% vs. 3%). In this population, RLS
symptoms occurred more than 10 years after narcolepsy onset and was less familial
and, in contrast to idiopathic RLS, not more prevalent in women [26]. Transient
RLS has been described in those undergoing spinal anesthesia [27]. Other second-
ary causes of RLS include myelopathy, Parkinson’s disease and diabetes. Medications
may also precipitate RLS symptoms. Common medications which can precipitate
RLS include tricyclic antidepressants, SSRIs, MAOIs, lithium, antihistamines and
dopamine antagonists. An exception is the antidepressant buproprion with its dop-
amine promoting activity it may benefit the symptoms of RLS. Though smoking is
generally considered an aggravating factor for RLS, there has been one case report
describing alleviation of RLS symptoms by cigarette smoking [28]. Caffeine and
alcohol also have been described as secondary factors [29, 30].

Management

Medications that can worsen RLS should be discontinued and secondary causes
should undergo evaluation and treatment as this may improve the degree of symp-
toms. For those found to have iron deficiency iron therapy is recommended. Vitamin
C may enhance iron absorption. Non-pharmacologic treatments include improving
sleep hygiene as well as daytime exercise, warm baths, leg massage and acupuncture.
Two studies, to date, have investigated the effectiveness of sequential compression
devices for the treatment of RLS [31, 32]. In a prospective, randomized, double-
blinded study, sham-controlled trial there was significant improvement in RLS sever-
ity and quality of life measures in those using the sequential compression device
compared to the sham devices. Complete relief occurred in one-third of the therapeu-
tic group in this study [32]. There has been one case reporting the improvement in
RLS symptoms with 4-week therapy with near-infrared light [33]. A subsequent
study, by the same group, with 34 volunteers reported significant improvement in
RLS symptoms in the near-infrared light treatment group compared to the control
group [34]. More research is necessary to investigate these and other potential non-
pharmacologic therapies. RLS has primarily been treated by four classes of medica-
tions which include dopaminergic agents, anticonvulsants, benzodiazepines and
opioids though other agents have been used (Table 18.3). An evidence-based review
produced by a task force commissioned by The Movement Disorder Society con-
cluded that levodopa, ropinirole, pramipexole, cabergoline, pergolide and gabapen-
tin were efficacious for the treatment of RLS while rotigotine, bromocriptine,
oxycodone, carbamazepine, valproic acid and clonidine were likely efficacious [35].
Levodopa/benserazide or levodopa/carbidopa at dosages of 100/25 to 200/50 mg is
considered efficacious for the treatment of RLS. The side-effect profile of levodopa
is favorable however problems with augmentation develop with higher doses and
longer treatment duration. The dopamine agonists ropinirole and pramipexole are
FDA approved for the treatment of RLS. Ropinirole (0.25–4 mg, mean 2 mg) and
pramipexole (0.75 mg) are efficacious for treating RLS in patients with moderate to
354 N.S. Undevia

Table 18.3 Treatment for RLS

Non-pharmacological treatments
Improved sleep hygiene
Exercise
Massage
Acupuncture
Sequential compression devices
Near-infrared light
Pharmacological treatments
Dopaminergic agents
Antiepileptics
Benzodiazepines
Opioids
Iron

severe symptoms. Several studies have demonstrated the effectiveness of the rotigo-
tine transdermal patch for treatment of RLS including a randomized, double-blinded,
placebo-controlled trial including 505 participants with moderate to severe RLS
[36–41]. Ergot derived dopamine agonists, including bromocriptine, pergolide and
cabergoline require special monitoring due to increased incidence of cardiac valvuar
fibrosis and other fibrotic side effects. While efficacious these agents are not currently
used commonly. Augmentation is the main complication of long-term dopaminergic
treatment of RLS and is characterized by an overall increase in severity of RLS
symptoms with earlier onset of symptoms, faster onset of symptoms and extension
of the symptoms to the upper extremities. Mild cases may be followed while in more
severe cases a change in treatment may be indicated. Ferritin may play a role as a
biomarker for patients likely to develop augmentation [42]. Side effects of dop-
aminergic agents include excessive daytime sleepiness, nausea, vomiting, hallucina-
tions and insomnia. Dopaminergic therapy for RLS has also been associated with
compulsive behaviors such as compulsive gambling and shopping. Antiepileptics
used in the treatment of RLS include carbamazepine, gabapnenin, pregabalin and
lamotrigine. Antiepileptics may be considered first line therapy in those with
concomitant neuropathy or painful leg symptoms. Gabapentin has been reported to
be as effective as ropinirole in improving the sensorimotor symptoms in idiopathic
RLS [43]. Pregabalin also has been demonstrated to improve RLS symptoms in dou-
ble-blinded, placebo-controlled trials [44, 45]. Of the benzodiazepines clonazepam
is the best documented for treatment of RLS. Side effect of these agents includes
sleepiness and tolerance. Opioids are used in the treatment of RLS however at suffi-
cient analgesic doses do cause a series of minor and major adverse effects including
sedation, fatigue and constipation. Short acting agents including hydrocodone, oxy-
codone, and codeine may be used for intermittent or nightly symptoms. For more
severe symptoms longer acting opioids including oxycodone, methadone or the
fentanyl patch should be used. Tramadol has also been used.
18 Movement Disorders 355

Periodic Limb Movement Disorder

Initially termed “nocturnal myoclonus” by the English neurologist Charles P

Symonds in 1953, the term periodic movements in sleep was suggested by
Coleman in 1980 [46, 47]. PLMD is characterized by periodic episodes of repeti-
tive, highly stereotyped, limb movements that occur during sleep (PLMS) and by
clinical sleep disturbance that cannot be accounted for by another primary sleep
disorder. PLMS typically involves the extension of the big toe, often in combina-
tion with partial flexion of the ankle, the knee, and sometimes the hip. Similar
movements can occur in the upper limb. They can occur individually in associa-
tion with arousals or awakenings from sleep. PLMS may occur unilaterally, alter-
nate between legs or occur simultaneously in both legs. Significant night to night
variability may be present.

Demographics

In a study of randomly selected community-dwelling persons 65 years and older,

the prevalence rate of PLMS was 45% [48]. Although most individuals with RLS
have PLMs, most people with PLMS do not have symptoms of RLS.

Diagnosis

The diagnosis of PLMD in adults according to the Second Edition of the ICSD-2
requires: (a) Polysomnography demonstrates repetitive, highly stereotyped, limb
movements that are: 0.5–5 s in duration, of amplitude greater than or equal to 25%
of toe dorsiflexion during calibration, in a sequence of four or more movements and
separated by an interval of more than 5 s and less than 90 s. (b) The PLMS index
exceeds 5/h in children and 15/h in most adult cases. (c) There is clinical sleep dis-
turbance or a complaint of daytime fatigue and (d) The PLMs are not better explained
by another current sleep disorder, medical or neurological disorder, mental disorder,
medication use, or substance use disorder (Table 18.4) [1].

Table 18.4 Diagnostic criteria for periodic limb movement disorder (PLMD)
Polysomnography demonstrates repetitive, highly stereotyped, limb
movements
The periodic limb movement index exceeds 15/h in most adult cases
Clinical sleep disturbance or daytime fatigue
Limb movements during sleep are not better explained by another disorder
356 N.S. Undevia

Associated Features

Patients often report history of sleep onset or maintenance problems, unrefreshing

sleep or excessive daytime hypersomnolence. PLMs have been associated with a
number of sleep disorders including narcolepsy, REM sleep behavioral disorder and
sleep apnea as well as with a number of neurologic disorders. Bed partner observa-
tions of leg movements may help in the clinical evaluation of PLMS. Polysomnography
is necessary to identify PLMS and to exclude sleep-related breathing disorders as
the cause of the PLMS. PLMS should also be distinguished from other movements
such as change in body position, stretching or leg cramps. Movements are reported
as an index of the number of leg movements per hour of sleep called the PLMS
Index. PLMS may produce no change in the EEG or associated arousal or may be
associated with K-complexes, K-alpha complexes, alpha activity or other evidence
of arousal. In a study of 23 patients with PLMs and/or RLS 60% of PLMS were
associated with microarousals, 4% were associated with slow wave activity and
36% showed no EEG changes. There was a prevalence of leg movements with
microarousals in stage N1 and N2 sleep while PLMS without microarousals were
prevalent in slow wave sleep [49]. PLMS are usually absent during REM sleep. Two
types of PLMS have been described. Type I has a peak frequency between midnight
to 3 a.m. followed by a decrease in late morning hours and is seen in those with RLS
and idiopathic PLMS. In Type II, leg movements are more evenly distributed
throughout the night and are associated with sleep-related breathing disorders, REM
sleep behavior disorder and narcolepsy.

Differential Diagnosis

The differential diagnosis includes sleep starts, normal phasic REM activity and
fragmentary myoclonus. Sleep starts are limited to the transition from wakefulness
to sleep and are shorter than PLMS. Normal phasic REM activity is usually associ-
ated with bursts of rapid eye movements and does not have the periodicity of PLMS.
Fragmentary myoclonus activity is briefer and is primarily an EMG diagnosis with
little or no visible movement.

Management

Similar to management of RLS, an investigation to identify secondary causes of

PLMs is recommended. Consideration should be given to discontinuing medications
that may contribute to PLMs. The decision to treat PLMS should be based on signs
of EEG arousal, disturbed nocturnal sleep or associated daytime fatigue. Medication
treatment is similar to that of RLS and includes dopaminergic agents, anticonvulsants,
18 Movement Disorders 357

benzodiazepines and opioids. Given that many patients may not be aware of PLMS,
assessment of response to therapy is dependent on improvement in sleep quality,
bed partner reports on frequency of leg movements and improvement in daytime
symptoms including fatigue. In some instances polysomnography performed
on treatment is required to assess response to therapy.

Sleep-Related Leg Cramps

Sleep-related leg cramps are painful sensations caused by sudden and intense invol-
untary contractions of muscles or muscle groups, usually in the calf or small mus-
cles of the foot occurring during the sleep period. These episodes may last up to a
few minutes, awakens the patient and interrupts sleep.

Diagnosis

The diagnosis of sleep-related leg cramps according to the Second Edition of the
ICSD-2 requires: (a) A painful sensation in the leg or foot is associated with sudden
muscle hardness or tightness indicating a strong muscle contraction. (b) The painful
muscle contraction in he legs or feet occurs during the sleep period, although they
may arise from either wakefulness or sleep. (c) The pain is relieved by forceful
stretching of the affected muscles, releasing the contraction and (d) The sleep-related
leg cramps are not better explained by another current sleep disorder, medical or
neurological disorder, medication use, or substance use disorder (Table 18.5) [1].

Demographics

Sleep-related leg cramps appear to occur at any age but are more common and fre-
quent in the elderly. In an epidemiologic study in children an overall incidence of
7.3% was reported [50]. In a general practice-based study of 233 people older than
age 60, almost one-third had cramps during the previous 2 months, this increased to
one-half in those older than 80. In addition, 40% had cramps more than 3 times a
week and 6% reported daily cramps [51]. A study of outpatient veterans found that

Table 18.5 Diagnostic criteria for sleep-related leg cramps

Painful sensation in leg or foot associated with strong muscle contraction
Painful muscle contraction occurs during the sleep period
Pain is relieved by forceful stretching of the affected muscles
Symptoms are not better explained by another disorder
358 N.S. Undevia

56% reported leg cramps [52]. Another study found that 50% of patients had leg
cramps and 20% reported leg cramps for over 10 years [53]. Sleep-related leg
cramps may appear or worsen during pregnancy and was reported in 75% women in
their third trimester of pregnancy in a study of 12 women [54].

Differential Diagnosis

The differential diagnosis of sleep-related leg cramps includes muscle strain, dysto-
nias, claudication, RLS, periodic limb movements and nocturnal myoclonus. The
pain associated with muscle strain is often associated with overuse or injury and
does not usually occur only at night. The pain associated with claudication is usu-
ally relieved by rest. RLS involves an urge to move the legs with temporary relief
with movement and not requiring stretching of the muscle. Periodic limb move-
ments occur during sleep and are not associated with pain or muscle hardening.
Muscle cramps may also be a feature of a number of other neurologic conditions
however these cramps are not usually restricted to nighttime or the legs alone.

Associated Features

During the cramp the muscles are firm and tender. Tenderness and discomfort in the
muscle may persist for several hours after the cramping. Delayed sleep onset and
awakenings from sleep are often present with persistent discomfort delaying return to
sleep. Patients may need to get out of bed to stand and stretch to alleviate symptoms.
Sleep-related leg cramps are not sleep stage specific as they may occur in any sleep
stage. Although sleep-related leg cramps are idiopathic in most individuals, a large
number of potential contributing factors have been reported. Medications that have
been reported to cause leg cramps include diuretics, nifedipine, statins B-agonists,
steroids, morphine, cimetidine, penicillamine, and lithium. Medical conditions associ-
ated with sleep-related leg cramps include uremia, diabetes, thyroid disease, hypopara-
thyroidism, hypomagnesemia, hypocalcemia, hyponatremia and hypokalemia.
Additional predisposing factors include vigorous exercise during the day, oral contra-
ceptive use, peripheral vascular disease and dehydration. Polysomnography is not
routinely recommended for the evaluation of sleep-related leg cramps but may show
bursts of increased electromyographic activity over the affected area.

Treatment

A careful history to identify and treat any precipitating factors is important in

patients with sleep-related leg cramps. Patients should be reassured regarding the
benign nature of the disease. Adjustment of possible contributing medications
18 Movement Disorders 359

should be considered. Cramps, once present, can be aborted by forcible dorsiflexion

of the foot with the knee extended. This is often discovered by patients while dealing
with cramps acutely at night and may be all that is required when sleep-related leg
cramps are infrequent. Passive massage or stretching may also help. An uncon-
trolled study of 44 patients determined that passively stretching the calf muscles 3
times a day for several days prevented cramps though a more recent randomized
controlled trial found this treatment to be ineffective [55, 56]. Pharmacological
treatment of leg cramps may be necessary when symptoms are severe and frequent.
A number of treatments have been investigated. Quinine, an alkaloid agent, reduces
the excitability of the motor end plate to nerve stimulation and increased the refractory
period of skeletal muscle contraction. It has been used to treat leg cramps since
1940 though there are significant concerns regarding the risk/benefit ratio with this
drug [57, 58]. Meta-analysis data regarding the efficacy of quinine have produced
conflicting data with one study reporting an 8.8% reduction in leg cramps and
another reported a 3.6% reduction [59, 60]. In a study of 27 male veterans, 13
reported at least a 50% decrease in the number of leg cramps with quinine treatment
[61]. In 1995 the FDA concluded that the risks of quinine outweighed any possible
benefit and ordered a stop to the marketing of quinine for prevention or treatment of
sleep-related leg cramps. They identified a 1 in 1,000 to 1 in 3,500 risk of potentially
fatal thrombocytopenia. If used, risks vs. benefits should be evaluated closely,
patients should be aware of the potential risks associated with quinine use and qui-
nine should be used cautiously at the lowest dose possible. Use of quinine containing
beverages including tonic water and bitter lemon should be discouraged due to
anecdotal reports suggesting that products containing quinine may produce neuro-
logical complications [62]. Quinine induced thrombocytopenia and hypersensitivity
reactions are among the most serious complication of quinine. Other rare complica-
tions include pancytopenia, hemolytic uremic syndrome and hepatitis. Quinine tox-
icity is also a significant concern. Naftidrofuryl oxalate, a vasodilator, significantly
reduced the frequency of cramps and increased the number of cramp free days by a
third in a double-blind, placebo-controlled trial in 14 patients [63]. Orphenadrine
citrate, an anticholinergic, reduced the frequency of leg cramps by a third in the
majority of patients in a double-blind crossover trial [64]. Verapamil 120 mg at
bedtime for 8 weeks resulted in an improvement in cramp symptoms in seven out of
eight patients during an uncontrolled study [65]. Magnesium was effective in treating
sleep-related leg cramps in pregnant women in a double-blind, randomized,
placebo-controlled study; however, no significant effect was seen in the study of
non-pregnant patients [66, 67]. Vitamin E did not reduce the frequency of leg cramps
in a randomized controlled crossover study [61]. In the only randomized, double-
blind, placebo-controlled study evaluating the efficacy of vitamin B complex capsules,
86% of the patients had prominent remission of leg cramps at 3 months compared
to placebo [68]. Several studies have demonstrated the effectiveness of gabapentin
in the treatment of leg cramps in those with neurologic conditions though its useful-
ness in idiopathic leg cramps remains unclear [69, 70]. The effectiveness of lido-
caine injection at the gastrocnemius trigger point and botulinum injection into calf
muscles for treatment of sleep-related leg cramps has also been reported [71, 72].
360 N.S. Undevia

Sleep-Related Bruxism

One of the first reports of bruxism was from Black in 1886; however, the term
bruxism was introduced by Miller in 1938 [73, 74]. Sleep-related bruxism is an oral
activity characterized by grinding or clenching of the teeth during sleep usually
associated with sleep arousals. Jaw activity during sleep includes tonic contractions
and rhythmic masticatory muscle activity (RMMA) that occurs at about 1 Hz.
Tooth-grinding sounds occur when these contractions are strong during sleep and
are present in about 20% of episodes [75].

Demographics

Bruxism has the highest prevalence in childhood decreases with increasing age.
One study reported an overall prevalence of 8% with a frequency of 13% in those
18–29 years of age and only 3% in older individuals [76]. No gender differences
have been found [77]. A familial pattern is seen in approximately 20–35% of patients
[78]. Moderate to severe tooth wear and jaw discomfort is seen in about 5–10% of
the population [75].

Diagnosis

The diagnosis of sleep-related bruxism according to the Second Edition of the

ICSD-2 requires: (a) The patient reports or is aware of tooth-grinding sounds or
tooth clenching during sleep. (b) One or more of the following is present: abnormal
wear of the teeth, jaw muscle discomfort, fatigue or pain and jaw lock upon awaken-
ings, masseter muscle hypertrophy upon voluntary forceful clenching and (c) The
jaw muscle activity is not better explained by another current sleep disorder, medi-
cal or neurological disorder, medication use, or substance use disorder (Table 18.6)
[1]. In routine polysomnography bruxism is suggested by a typical EMG artifact
recorded on electroencephalographic recordings. The EMG of bruxism shows either
a phasic pattern of activity at 1 Hz frequency lasting 0.25–2 s, sustained tonic activ-
ity lasting longer than 2 s, or a mixed pattern.

Differential Diagnosis

Nocturnal jaw movements can be associated with other disorders including partial
complex or generalized seizures, idiopathic myoclonus and parasomnias such as
sleeptalking and must be distinguished from sleep-related bruxism.
18 Movement Disorders 361

Table 18.6 Diagnostic criteria for sleep-related bruxism

Tooth-grinding sounds or tooth clenching during sleep
One or more of the following are present: abnormal wear of the teeth, jaw muscle discomfort,
fatigue or pain and jaw lock upon awakening and/or masseter muscle hypertrophy upon
voluntary forceful clenching
Jaw muscle activity is not better explained by another disorder

Associated Features

Sleep-related bruxism can lead to abnormal wear of the teeth, tooth pain, jaw muscle
pain or temporal headache. Fractured teeth and buccal lacerations and temporo-
mandibular joint pain can also occur as a consequence of sleep-related bruxism.
Sleep disruption may also occur. Over time, hypertrophy of the facial muscles can
develop. Sleep bruxism has been attributed to several etiologies though the theory
that malocclusion was the cause has fallen out of favor. It is thought that a combi-
nation of psychological stress and specific personality traits may play a role. Other
associated conditions include obstructive sleep apnea, gastroesophageal reflux,
certain medications including serotonin reuptake inhibitors and amphetamines.
Bruxism is frequently associated with Down’s syndrome, autism and attention
deficit hyperactivity disorder (ADHD) [79, 80]. Bruxism can occur during any
sleep stage, including REM sleep, but is most often seen during arousals from
stage N2 sleep.

Management

Therapies for sleep-related bruxism can be divided into orthopedic, behavioral and
pharmacologic. Non-pharmacological treatments include occlusal bite splints which
provide protection against tooth damage. Patients should be followed by a dentist
who can monitor dental wear. Excessively worn teeth may need to be crowned.
Obstructive sleep apnea is a risk factor for sleep-related bruxism and successful
treatment of sleep disordered breathing may eliminate bruxism during sleep [81].
Psychological counseling may be helpful in stress-related cases of bruxism.
Benzodiazepines and muscle relaxants may be necessary in more severe cases
though they may contribute to daytime sleepiness. Randomized, controlled and
double-blind studies investigating the pharmacologic therapies for sleep-related
bruxism are lacking. Other medications that have been reported to be used for brux-
ism include propranolol, l-dopa, pergolide, bromocriptine, and gabapentin [82–85].
Botulinum toxin injection in the masseter muscles resulted in significant clinical
improvement in a group of 18 individuals with severe, recalcitrant, bruxism. The
authors suggested botulinum toxin therapy in those who had not responded to con-
ventional therapy [86].
362 N.S. Undevia

Sleep-Related Rhythmic Movement Disorder

Described in 1905 by Zappert as “jactatio capitis nocturna” and independently by

Cruchet as “rhythmie du sommeil” the term “rhythmic movement disorder” was
adopted by the ICSD in 1990. Sleep-related RMD is characterized by repetitive,
stereotyped, and rhythmic motor behaviors that occur predominantly during drowsi-
ness or sleep and involve large muscle groups. Initially classified as a sleep wake
transition disorder, the revised ICSD reclassifies RMD under the heading of sleep-
related movement disorders. Sleep-related rhythmic movements are normal in
children and a disorder should be diagnosed when significant consequences are
present. RMD is typically seen in infants and children. Body rocking, head banging
and head rolling are subtypes of RMD. Combined types may also be observed.

Demographics

SRMD is most commonly observed in children. The incidence of RMD is 66% in

9-month-old infants and decreases to 8% in 4-year olds [87]. In one study, head
banging persisted beyond the age of 4 in 30% of patients but usually ended by age
10 [88]. Though most common in children RMD has also reported in adolescents
and adults. When observed in older children and adults there has been a reported
association with mental retardation, autism or other pathology though cases in
adults of normal intelligence have been reported [89, 90]. No sex differences have
been found in patients with RMD.

Diagnosis

RMD can be recognized by its characteristic clinical features. However, in some

instances polysomnography may be useful. The diagnosis of RMD according to the
Second Edition of the ICSD-2 requires: (a) The patient exhibits repetitive, stereo-
typed and rhythmic motor behaviors. (b) The movements involve large muscle
groups. (c) The movements are predominantly sleep related, occurring near nap or
bedtime, or when the individual appears drowsy or asleep. (d) The behaviors result
in a significant complaint as manifest by at least one of the following: interference
with normal sleep, significant impairment in daytime function, self-inflicted bodily
injury that requires medical treatment and (e) The rhythmic movements are not better
explained by another current sleep disorder, medical or neurological disorder, mental
disorder, medication use, or substance use disorder (Table 18.7) [1].
18 Movement Disorders 363

Table 18.7 Diagnostic criteria for sleep-related rhythmic movement disorder (RMD)
Repetitive, stereotyped and rhythmic motor behaviors
Movements involve large muscle groups
Movements are predominantly sleep related or occur near nap or bedtime
A significant complaint such as interference with sleep, significant impairment in daytime
function or self-inflicted bodily injury is present
Rhythmic movements are not better explained by another disorder

Associated Features

While polysomnographic studies have shown rhythmic movements to occur most

often in stage N1 and N2 sleep there have been reports of RMD in REM and slow
wave sleep [90, 91]. In the case or RMD occurring in REM sleep, concurrent REM
sleep behavior disorder has not been reported [90, 92]. The most common subtypes
of RMD are body rocking (19.1%), head banging (5.1%), and head rolling (6.3%).
Body rolling, head rolling and leg banging subtypes have also been described. As
noted previously patients may also have combinations of the noted subtypes. Sleep
is not fragmented by RMD and sleep stages do not usually change as a result of
movement. RMD does not usually interrupt sleep and patients have minimal recall.
A review of ten subjects with RMD persisting beyond 5 years of age found a strong
association with ADHD [90]. Several studies have reported RMD in adults with
obstructive sleep apnea with RMD initiated by arousals at the termination of the
apneas. Improvement in RMD was noted with treatment of obstructive sleep apnea
with CPAP [93–95]. Polysomnogram is useful to uncover RMD aggravated by
another sleep disorder. On polysomnogram the frequency of movements ranges
from 0.5 to 2 Hz.

Differential Diagnosis

The clinical history of RMD is usually clear though the differential diagnosis of
RMD includes PLMD and sleep-related epilepsy. In contrast to PMLD, the
movements of RMD are continuous for short periods of time rather than periodic
jerking. Polysomnographic findings of RMD may be confused with bruxism,
thumb sucking and rhythmic sucking of a pacifier. RMD should also be distin-
guished from akathisia which is not sleep related and involves a feeling of gen-
eralized restlessness.
364 N.S. Undevia

Treatment

For the majority of RMD patients no treatment other than reassurance is required.
Parents should be advised that neurologic damage in unlikely and that the child will
outgrow the problem. RMD has rarely been associated with head injury, carotid artery
dissection and ocular injury [96–98]. In cases where there is concern regarding serious
injury, treatment is warranted. Hypnosis was reported as an effective treatment in a
26-year-old woman with body rocking since infancy [99]. Other treatments that have
been used include behavioral interventions [100]. Almost complete resolution of rhyth-
mic movements was noted in six children with 3 weeks of controlled sleep restriction
with hypnotic administration in the first week [101]. Tricyclic antidepressants have
also been used to treat RMD. One study documented failure of doxepin, amitriptyline
and imipramine while another reported success with imipramine [102, 103]. In one
report citalopram at a dose of 20 mg was effective in eliminating head banging in a
5-year old with ADHD [104]. Several studies have demonstrated the utility of low dose
clonazepam. Clonazepam at a starting dose of 0.5 mg was not sufficient to decrease the
intensity or frequency of events but 1 mg was found to be effective [105, 106].

Conclusion

Sleep-related movement disorders include a varied group of diseases which are

quite prevalent and can cause significant sleep disturbance, impairment in daytime
functioning and compromise quality of life. These disorders are frequently encoun-
tered yet may be confused or misdiagnosed by health care professionals. Increasing
awareness of these conditions is necessary to allow for prompt identification and
management as this can significantly improve quality of life.

Summary of Keypoints

• Restless Legs Syndrome (RLS) is a common sensorimotor disorder character-

ized by a distressing urge to move the legs and sometimes other parts of the body
such as the arms. RLS affects approximately 10% of US adults. Difficulty falling
asleep may frequently be associated with moderate-to-severe RLS.
• The diagnosis of RLS is based on clinical criteria and does not require a polysom-
nogram unless an additional sleep disorder is suspected.
• The majority of cases of primary RLS are hereditary (autosomal dominant).
Causes of secondary RLS include iron deficiency, peripheral neuropathy, uremia
associated with renal failure and pregnancy. Common medications which can
precipitate RLS include tricyclic antidepressants, SSRIs, MAOIs, lithium, anti-
histamines and dopamine antagonists. RLS affects approximately 10% of US
adults.
18 Movement Disorders 365

• RLS Diagnostic Criteria

1. Uncomfortable sensation in the legs associated with an urge to move
2. Symptoms are worse at rest
3. Symptoms are temporarily relieved by movement
4. Symptoms are worse or only occur at night
• Medications that can worsen RLS should be discontinued and secondary causes
should be evaluated and treated.
• Management strategy consists of discontinuation of medications that can worsen
RLS, treatment of secondary causes of RLS such as iron deficiency, conservative
treatment and pharmacologic treatment. Four classes of medications have been
used for the treatment of RLS, including dopaminergic agents, anticonvulsants,
benzodiazepines and opioids.
• Periodic limb movement disorder (PLMD) is a sleep disorder characterized by
rhythmic movements of the limbs during sleep, involving the legs, but upper
extremity movements may also occur. Movements tend to cluster in episodes that
last anywhere from a few minutes to several hours.
• The causes of PLMD are unknown. However, people with a variety of medical
problems, including Parkinson’s disease and narcolepsy, may have frequent peri-
odic limb movements in sleep. PLMD may be caused by medications, most nota-
bly, antidepressants. Periodic Leg Movements (PLMs) occur in at least 85% of
people with RLS. PLMs are not usually seen in REM sleep.

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Chapter 19
Perioperative Care of Patients with Obstructive
Sleep Apnea Syndrome

Haven R. Malish and Peter C. Gay

Keywords Perioperative complications • Postoperative monitoring • Obstructive

sleep apnea • Questionnaires • Perioperative guidelines • Sleep apnea guidelines
• Postoperative CPAP • Hospital sleep apnea

Introduction

Patients with obstructive sleep apnea (OSA) have an intrinsic defect where disfavorable
anatomic features, combined with increased airway resistance, leads to airway com-
promise when there is an insufficiently countered net upper airway (UA) dilator
muscle force [1]. Patients with OSA are therefore more vulnerable during anes-
thesia and sedation, as the effects of loss of wakefulness and supination are com-
pounded by drug-induced depression of all muscle activity and of arousal responses,
so that they cannot respond well to hypoxemia, hypoventilation, or even asphyxia
[2, 3]. Conversely, those with difficult airways during anesthesia, either because of
problems with maintenance of airway patency without tracheal intubation or because
anatomic compromise makes intubation itself problematic, are at increased risk of
OSA. As such, difficulty with airway maintenance during anesthesia should prompt
further investigation for the possibility of OSA [4, 5]. These relationships are clinically
relevant. Early identification of patients with OSA may forewarn the clinician of
potential difficulty with airway maintenance intra- and postoperatively, perhaps
influencing choice of anesthetic technique and postoperative monitoring environment.
Anticipation of perioperative issues in those with known OSA as well as screening

H.R. Malish
Sleep Medicine, Mayo Clinic, Rochester, MN, USA
P.C. Gay (*)
Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 371
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_19,
© Springer Science+Business Media, LLC 2012
372 H.R. Malish and P.C. Gay

for those with suspected sleep apnea is now urged by the American Academy of
Sleep Medicine (AASM) and the American Society of Anesthesiologists (ASA)
[6, 7]. As will be discussed in much more detail below, perioperative complications
occur more commonly in those with OSA and can have significant impact on patient
outcomes [8]. We will first review the factors that may contribute to increased risk
of complications in surgical patients as it pertains to those with OSA. Subsequently,
we will discuss preoperative approaches to those with and without known OSA,
followed by intra- and postoperative management strategies to optimize care of
patients with OSA.

Preoperative Risk Assessment and OSA Screening Protocols

Factors Contributing to Increased Risk of Complications

in Surgical Patients

As introduced earlier, the mechanism of OSA has been related to increased UA

collapsibility, reduction in UA size, alterations in craniofacial structure, and enlarge-
ment of the surrounding soft tissue [9–11]. During wakefulness, the UA muscles
maintain patency despite negative intraluminal inspiratory pressures. During sleep,
the UA muscles behave like a collapsible tube that has been likened to a Starling
resistor [12]. The airway will collapse if intrathoracic and intraluminal pressure
decreases beyond the critical opening pressure, or Pcrit. Normal subjects, primary
snorers, patients with obstructive sleep hypopnea, and patients with OSA are distin-
guished by progressively higher and more positive Pcrit values, signifying progres-
sively higher likelihood of UA collapse [13, 14].
Increased UA collapsibility can contribute to the increased perioperative risk
in patients with OSA and can be directly influenced by choice of perioperative
medications. Sedatives, anesthetics, and narcotics reduce UA dilator tone and inhibit
protective airway reflexes, central ventilatory drive, and mechanisms of arousal
[15]. These effects mimic sleep, which can lead to exacerbation of the apneas and
hypopneas and this population is already predisposed to this. Also, previously
obstructive sleep-disordered breathing events may now become central or complex
under the influence of opiates [16]. Intubation and postoperative edema, nasal
packing, nasal tubes, and hematomas can narrow the UA. The result is a reduction
in the amount of collapse necessary to cause apneas and hypopneas. The require-
ment for supine positioning perioperatively is another contributor to worsening of
OSA, especially in those whose OSA is known to be supine predominant [17].
While supine positioning may especially be a concern for those going home unob-
served the same day of surgery, it still poses a challenge in the hospitalized patient
and can amplify the above-mentioned risk factors.
The inpatient setting plays host to additional risks for OSA patients. It is well
known that hospitalized patients can suffer from sleep deprivation in the
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 373

form of sleep fragmentation, circadian disruption, and sleep restriction [18–21].

Postoperative OSA patients are more vulnerable to medical problems when sleep
is denied or further compromised by sleep-disordered breathing [22]. Whereas
there is a reduction in REM sleep in most hospitalized patients, near-obliteration of
REM can initially occur in postsurgical patients which is significantly related to an
opioid effect [23].
Personal observation tells us that patients often discontinue use of positive airway
pressure (PAP) perioperatively. Patients at times may have PAP appropriately held
by their caregivers in the setting of their illness for various reasons. Forgetting to
bring the PAP device, failure of the health care provider to restart postoperative
PAP, and failure of the hospital to provide equipment can also contribute.

Morbid Obesity and OSA

Obesity is one of several predictors for OSA [24]. Aside from the problems with
redundant pharyngeal tissue and airway collapse, abdominal obesity has mechanical
effects on the UA. Studies have demonstrated that the reduced lung volume asso-
ciated with obesity contributes to poor UA function in OSA patients [25]. Support
for this interaction comes from experimental findings where abdominal compres-
sion during sleep in OSA patients worsened UA collapse [26]. Historically, the
intubation of the morbidly obese patient with OSA and a suspected difficult airway
was most commonly managed with an awake, fiber-optic technique. Recent studies
have described a 96% success rate when using an alternative airway device called
the intubating laryngeal mask airway (ILMA) in morbidly obese patients [27, 28].
In one study, 100% of the morbidly obese patients were successfully ventilated
through the LMA [29]. Whether these promising outcomes persist when using an
ILMA in the morbidly obese with OSA is not known. Intervention protocols as they
relate to PAP therapy and gastric bypass surgery patients will be discussed later.

Preoperative Evaluation

Preoperative Screening for Suspected OSA

Surgical patients usually undergo preoperative evaluation a few days or weeks prior
to their surgery. In 2006, the ASA published guidelines recommending patients be
screened for risk of OSA before their surgery [30]. While a number of question-
naires had been developed to aid in identifying patients at risk for OSA, most of
these had been first validated in the outpatient sleep laboratory setting. In the last
several years, questionnaires had been developed with validation in the preopera-
tive setting [31].
374 H.R. Malish and P.C. Gay

The Berlin Questionnaire

The Berlin questionnaire allows the patient to self-report five questions on snoring,
three on excessive daytime sleepiness, one on sleepiness while driving, and one
inquiring history of hypertension [32]. It is one of the commonly known question-
naires for OSA and has been validated in the setting of primary care. Age, gender,
weight, height, and neck circumference are also recorded. The Berlin question-
naire’s predictive performance is patient populations dependent. In a primary care
setting of 744 patients, it carries a sensitivity of 0.89, specificity of 0.71, and half of
the high-risk patients it identifies are subsequently found to have OSA (at AHI >15)
by polysomnography. The Berlin Questionnaire identified 24% of patients pre-
senting for elective surgery as high risk of a pool of 318 [33]. A study screening
preoperative patients using the Berlin questionnaire determined it had a sensitivity
of 69% with a specificity of 56% in surgical patients [34]. Even if the Berlin ques-
tionnaire has moderately high sensitivity and specificity for identifying OSA in the
preoperative setting, the number of questions and the complicated scoring proce-
dure may be too laborious for anesthesiologists and their patients.

The American Society of Anesthesiologists’ Checklist

In the recent guidelines for the perioperative management of patients with OSA, the
ASA taskforce on OSA developed a 14-item checklist to assist anesthesiologists in
identifying OSA [30]. Patients endorsing symptoms or signs in two or more of the
three categories (physical characteristics, history of airway obstruction during sleep,
and complaints of somnolence) are considered high risk of having OSA. The major
drawback to this screening tool is the time commitment because the checklist needs
to be completed by the clinician. The ASA check list has been validated in surgical
patients to have sensitivities of 72, 79, and 87% at AHI cutoff levels of >5, >15, and
>30 events/h, respectively [34]. The same validation study also found the ASA
checklist’s sensitivity and specificity in predicting OSA in surgical patients similar
to the STOP questionnaire discussed below.

The STOP Questionnaire

A condensed modification of the questions in the Berlin survey, the STOP ques-
tionnaire was developed and validated to facilitate the widespread usage of an
OSA screening tool in surgical patients (S: Snore loudly, T: daytime Tiredness, O:
Observed to stop breathing during sleep, P: high blood Pressure). The sensitivity
of the STOP questionnaire at an AHI of >15 and >30 events/h cutoff levels was 74
and 79%, respectively, with specificity at similar AHI levels of 53 and 49%,
respectively [35].
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 375

The STOP-Bang Model

When additional factors were included, the STOP-Bang Questionnaire had the highest
sensitivity, especially for patients with moderate to severe OSA. This combined
version of the STOP-Bang Questionnaire added demographic and physical features
(B: BMI >35 kg/m2, A: Age >50 years, N: Neck circumference >40 cm, G: male
Gender). The use of the STOP-Bang Questionnaire improved the sensitivity to 93, and
100% at AHI cut-offs of >15 and >30, respectively, making it highly sensitive and an
ideal screening tool. The specificity of the STOP-Bang Questionnaire at similar AHI
levels, however, was only 43 and 37%, respectively. In the preoperative clinic, the
STOP Questionnaire was used to screen 211 patients, 28% of whom were classified as
being at high risk of OSA [35]. Ramachandran and Josephs [36] analyzed the accu-
racy of clinical screening methods in the diagnosis of OSA in a meta-analysis. The
authors identified 26 different clinical prediction tests with 8 in the form of question-
naires and 18 algorithms, regression models, or neural networks. The authors con-
cluded severe OSA can be predicted by questionnaires and clinical tests with a high
degree of accuracy. The Berlin questionnaire, the Sleep Disorders Questionnaire,
morphometry (Kushida index) [37] and the combined clinical–cephalometry model
(Battagel) [38] were the most accurate questionnaires and clinical models. However,
they warned that the high degree of heterogeneity and false negative rate with all
questionnaires and most clinical prediction models makes it possible that a significant
proportion of patients with OSA could still be missed by all questionnaires and most
of the clinical models. The metaregression analysis revealed that clinical models, log
equations, combined techniques, cephalometry, and morphometry were significant
test characteristics, whereas body mass index, history of hypertension, and nocturnal
choking are significant test elements in the more accurate prediction models.

Sleep Apnea Clinical Score

A different simple OSA screening questionnaire, called the Sleep Apnea Clinical
Score (SACS) was validated in the outpatient sleep laboratory environment and
shown to have a high positive predictive value for OSA [39]. The SACS score was
initially validated in postsurgical patients to identify patients who desaturated in the
postoperative hospital ward area [40]. A large follow-up prospective study enrolled
nearly 700 patients using the SACS and showed that a higher risk of OSA (32% of
all patients) was associated with a much higher likelihood of a postoperative 4%
oxygen desaturation index (ODI) >10 events/h and recurrent postanesthesia care
unit (PACU) respiratory events [41]. Subsequent postoperative hospital ward epi-
sodes of respiratory complications were also associated with a high SACS (odds
ratio 3.5, P < 0.001), especially if they also had recurrent respiratory events in the
PACU during 90 min of observation, whereby the likelihood of a postoperative
respiratory event was markedly increased (odds ratio 21.0, P < 0.001). There was no
significant benefit with the SACS questionnaire in predicting cardiac complications
or prolonged hospital stay.
376 H.R. Malish and P.C. Gay

Suspected OSA patient Known OSA patient

Screening using STOP or Severity Assessment from History

STOP-Bang questionnaire or Polysomnography

High risk of OSA Low risk of OSA Moderate or

≥ 2 on STOP ≤ 2 on STOP Mild OSA
AHI 5 1 15 Severe OSA
≥ 3 on STOP-Bang ≥ 3 on STOP-Bang AHI >15
Oximetry ≥ 94 %
on room air Oximetry < 94%
on room air

Major Elective Surgery &

Significant Comorbidities Changes is OSA Status
• Heart failure
• • Recent exacerbation of
Arrhythmias OSA symptoms
• Uncontrolled hypertension • Non-compliant to PAP
• Cerebrovascular disease Rountine management. therapy‡
• Metabolic syndrome No peroperative PAP • Recently undergone
• Obesity with BMI > kg/m2 therapy required. OSA-related surgery
• Lost to sleep medicine
follow-up

No Yes

Yes No

Possibility of Consider
moderate preoperative referral
OSA: to sleep medicine
Perioperative physician, Preoperative PAP
OSA polysomnography, therapy‡,
precautions and PAP therapy‡. Perioperative OSA
precautions

Fig. 19.1 An approach to those with suspected or known obstructive sleep apnea (OSA) prior to
surgery in the ambulatory setting. ‡ Positive airway pressure (PAP) therapy may include continu-
ous, bilevel, or autotitrating PAP (adapted with kind permission from Springer Science + Business
Media [42])

The decision regarding which screening tool is most suitable lies with the
clinicians and their institutional experience. Optimal preoperative evaluation
takes into account the risk of the surgery as well as the risk of the patient having
undiagnosed OSA [42]. The left side of Fig. 19.1 summarizes a preoperative
approach in the suspected OSA patient. Those with ³2 on STOP or ³3 on STOP-
Bang criteria are considered high risk of having undiagnosed OSA. If a high-risk
patient is presenting for major elective surgery and has significant comorbidities
suggestive of long-standing severe OSA, the anesthesiologist should consider a preop-
erative referral to the sleep physician and a recommendation for a polysomnogram
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 377

or a multichannel home sleep test if resources permit. A timely and early consult
would allow the sleep physician adequate time to prepare a perioperative manage-
ment plan, which may include a period of home PAP treatment. Major elective
surgery may have to be deferred in patients with a high clinical suspicion of severe
OSA with systemic complications. Ultimately, the decision for further preoperative
sleep study testing will depend on the clinical judgment and expertise of the attend-
ing physician, taking into account the patient-specific and logistical considerations
in their totality.
On the other hand, there may be patients who are at high risk according to the
OSA screening questionnaires, but who otherwise are without significant comor-
bidities and are ambulatory surgery patients or at least not scheduled to undergo
major surgery [43]. Some of these patients may have had uneventful anesthetics in
the past. These “at risk” patients may represent false positives on screening or
represent patients with less severe OSA (AHI <15). A positive screening test would
raise awareness and alert the anesthesiologist to undertake perioperative precau-
tions for possible OSA, as discussed later in the chapter. It can be assumed that these
patients possibly have moderate to severe OSA, and if subsequent intraoperative
(e.g., difficult airway) [44] or postoperative events (PACU recurrent respiratory
events) [41] suggest a higher probability of OSA, a polysomnography, and a sleep
physician referral after the surgery may be indicated. Due to the high sensitivity and
negative predictive value of the OSA screening tools, the incidence of false nega-
tives should be low. Therefore, patients who are at low risk of OSA (£3 positive
responses on STOP-Bang) are unlikely to have OSA. These patients may expectedly
be managed with routine perioperative care.

Preoperative Evaluation of Known OSA

A preoperative evaluation approach for known OSA patients is illustrated on the

right side of Fig. 19.1. To start, the diagnosis and severity of OSA should be
confirmed. Long-standing OSA may have systemic complications, including
hypoxemia, hypercarbia, polycythemia, and cor pulmonale. Pulse oximetry may
be a simple screening tool in the preoperative clinic. Some advocate that an oxygen
saturation value of <94% on room air in the absence of other causes should be an
alert flag for possible severe long-standing OSA [42]. The possibility of comor-
bidities, such as uncontrolled hypertension, arrhythmias, cerebrovascular disease,
heart failure, metabolic syndrome, and obesity should be pursued. The use of PAP
devices (continuous PAP, bi-level PAP, auto-titrating PAP) and the compliance to
PAP therapy should be assessed for those who have been prescribed PAP therapy.
It may be necessary to refer some patients with known OSA to the sleep medicine
physician for preoperative reassessment, especially patients who have been lost to
sleep medicine follow-up and are noncompliant with therapy, those who have had
recent exacerbation of OSA symptoms, and those who have undergone OSA-
related airway surgery.
378 H.R. Malish and P.C. Gay

Preoperative OSA Optimization

Reinitiation of preoperative PAP in the noncompliant OSA patient should be

considered, although evidence of its efficacy is lacking in this preoperative context
[45]. Patients with moderate and severe OSA who have been on PAP therapy should
continue PAP therapy in the preoperative period [30]. The intraoperative anesthesia
team should be alerted in advance, and perioperative OSA precautions should be
undertaken. Some of these measures would include anticipating possible difficult
airway experiences, the use of short-acting anesthetics agents, opioid minimization,
full reversal of neuromuscular blockade verified prior to extubation, and extubation
in a nonsupine position. It is unclear from the current literature if mild OSA (AHI
5–15) would be a significantly worse disease entity under anesthesia and in the
perioperative period. Based on expert opinion referenced earlier, patients with mild
OSA would not require preoperative PAP therapy. Mild OSA patients without respi-
ratory events in the PACU may be managed with routine perioperative care.

Intraoperative OSA Management

Choice of Anesthetics/Anesthetic Technique

There are numerous reviews on the subject of anesthetic management of OSA

patients [46–49] that emphasize that the type of anesthesia may have differential
impact on the respiration of patients. Despite these reviews, there are no randomized
controlled trials of the safety of various anesthetics in the perioperative period.
As mentioned previously, different analgesics have different margins of safety and
result in varying levels of respiratory depression. A relatively recent study [50] has
documented the impact of propofol on UA collapsibility by investigating the rela-
tionship between varying concentrations and the critical airway closing pressure or
Pcrit discussed earlier. The use of healthy individuals (not patients with OSA) as
subjects coupled with the lack of a randomized controlled design is a significant
limitation of this study. Nevertheless, the findings highlight that a carefully chosen
concentration of anesthetic may play an important role in the airway management
of OSA patients.
An important consideration in the choice of inhaled anesthesia is the presence of
any carryover anesthetic effects into the postoperative period that could impair res-
piration and/or enhance the deleterious respiratory effects of analgesics. In OSA
patients undergoing UPPP, there was delayed recovery in those patients receiving
isoflurane vs. propofol [51]. Propofol anesthesia was found to result in better
oxygen saturation in the first postoperative hour and more rapid recovery of
spontaneous breathing vs. isoflurane. Again, these studies were not done on OSA
patients. Short-acting anesthetics, such as remifentanil, have also been shown to
result in a rapid postoperative recovery, better oxygen saturation profile, and shorter
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 379

postoperative length of stay [52, 53]. Also, morbidly obese patients who underwent
major abdominal surgery awoke significantly faster after desflurane than after sevo-
flurane anesthesia. The patients anesthetized with desflurane had higher oxygen
saturation on entry to the PACU [54].
Premedication sedatives, especially benzodiazepines, such as flunitrazepam or
midazolam, have been shown to cause postoperative airway obstruction [55]. In this
study, 12 patients did not have a premorbid history of OSA but were observed to
snore loudly postoperatively. Conversely, some premedication drugs have been
shown to be beneficial in OSA patients. In a case report of a morbidly obese woman
with tracheal stenosis, dexmedetomidine, an alpha-2 adrenergic agonist, was used
as a premedication due to its anxiolytic and sedative properties. The benefit of dex-
medetomidine is the lack of significant respiratory depression within the clinical
dose range. Similarly, in a randomized controlled trial, orally administered cloni-
dine was found to reduce the propofol dose required for induction of anesthesia
[56]. Unfortunately, there are no trials of the efficacy of varying premedication
drugs in OSA patients undergoing surgery, but the above studies illustrate their
potential importance.

Increased Risk of Difficulty with Tracheal Intubation

Difficult tracheal intubation and OSA seem to share similar etiological pathways
that explain the predisposition to UA abnormalities. A retrospective case-controlled
study of 253 patients was conducted to determine the occurrence of difficult intuba-
tion in OSA patients [57]. The OSA patients were matched with controls of the
same age, gender, and type of surgery. Difficult intubation was assessed by laryn-
goscopy using the Cormack and Lehane classification [58]. Difficult intubation was
found to occur 8 times as often in OSA patients vs. controls (22% vs. 3%, P < 0.05).
In OSA patients undergoing ear, nose, and throat surgery, a 44% prevalence of dif-
ficult intubation has similarly been reported [59]. Furthermore, patients with severe
OSA (AHI >40) were found to have a much higher prevalence of difficult intubation
[60]. A study of more than 1,500 nonobese and obese patients concluded that
increased age, male gender, pharyngo-oral pathology, and the presence of OSA are
all associated with a more frequent occurrence of difficult intubation [61].
Conversely, patients with difficult tracheal intubation have been shown to be at
greater risk of having OSA [4]. In a small retrospective study of 15 patients with
difficult intubation, 53% (8 of 15) of patients were diagnosed with OSA. In a pro-
spective study, 66% of patients with difficult intubation were subsequently found to
have AHI >5 [5]. These reports suggest that anesthesiologists should refer patients
with difficult intubation for PSG sleep investigation of OSA. Apart from the above-
mentioned studies, there is no research investigating the causal and anatomical
relationship between OSA and difficult tracheal intubation and the implications
for perioperative management. Despite the higher prevalence of OSA in patients
with difficult intubation, it needs to be determined whether it is cost effective for all
380 H.R. Malish and P.C. Gay

patients with difficult intubation to undergo a diagnostic sleep study and if

preoperative continuous PAP (CPAP) treatment could ameliorate the difficulty
with tracheal intubation.

Postoperative OSA Management

Postoperative Pain Control

Postoperative analgesia can adversely influence respiration in surgical patients with

OSA. In a retrospective study of 1,600 patients, not specifically OSA patients, who
had received postoperative patient-controlled analgesia with IV opioids, eight cases
of serious respiratory depression were reported [62]. Contributing factors were the
concurrent use of a background infusion of opioids, advanced age, concomitant
administration of sedative or hypnotic medications, and a preexisting history of
sleep apnea. Two retrospective reviews of more than 1,000 surgical patients
indicated that postoperative respiratory depression after morphine-based patient-
controlled analgesia was observed to occur in about 1–2% of patients [63, 64]. This
respiratory depression occurred between 2 and 31 h after initiation of the IV patient-
controlled analgesia [63] indicating the need for extended diligent patient
monitoring.
A review conducted to identify the risk factors for respiratory depression sub-
sequent to patient-controlled analgesia concluded that there is no single indicator
for respiratory depression but that OSA, whether suspected or verified by patient
history, is one of the risk factors for respiratory depression [65]. Other factors
include older age, hepatic, pulmonary, or cardiac disease, concurrent use of central
depressants, obesity, and higher bolus doses of patient-controlled analgesia.
There are no prospective randomized studies examining the respiratory effect of
patient-controlled analgesia in OSA patients. In general, the consensus is that opioids
are to be avoided in OSA patients, if possible, especially when they undergo UA
surgical treatment for OSA [66]. The ASA guidelines recommend regional anesthe-
sia to reduce the possibility of negative adverse events associated with systemic
opioids; however, there is little outcome-based evidence to support this [67]. A multi-
modal approach with combinations of analgesics from different classes and different
sites of analgesic administration is a prudent strategy for perioperative pain man-
agement [68–70]. Such an approach may include peripheral nerve block catheters
or neuro-axial catheters dispensing local anesthetic agents (without opioids) and
opioid-sparing analgesic agents, such as nonsteroidal anti-inflammatory drugs,
COX-2 inhibitors, acetaminophen, pregabalin, tramadol, and dexamethasone [71].
Other novel approaches, such as ketamine, clonidine, or gabapentin can be used
[56, 68–70]. Ketamine may have a stabilizing effect on the UA [72]. In a case report,
the nonopioid sedative dexmedetomidine [73] has been shown to reduce the need
for postoperative opioids. More recently, it was demonstrated in a double-blinded,
placebo-controlled, crossover study that opioid-induced ventilator depression can
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 381

be selectively antagonized in humans by co-administering ampakine [74]. Other

techniques that avoid medication, such as transcranial magnetic stimulation [75] are
also being investigated. A major drawback of these studies is that they are predomi-
nantly case reports. Unfortunately, there are no studies comparing the safety and
efficacy of different anesthesia technique, general anesthesia, regional anesthesia,
or monitored anesthesia care in OSA patients undergoing surgery or studies on
different analgesic or adjuvants.

Postoperative Monitoring

Oximetry

Anesthesiologists regard continuous pulse oximetry monitoring in the perioperative

arena as a standard of practice and presumably can prevent postoperative complica-
tions and improving patient outcomes. Clinicians naturally assume that corrective
measures can be initiated to resolve postoperative hypoxemia to the benefit of
patients. Pedersen et al. [76] performed a medical literature search for randomized
controlled trials conducted during the perioperative period of patients using manda-
tory pulse oximetry or not. The authors asked whether pulse oximetry could identify
events that led to the prevention of adverse outcomes. The search provided data
from nearly 23,000 patients in five reports and as might be expected, the pulse
oximetry group showed that oxygen saturation was reduced in the operating room
and particularly in the PACU. No statistically significant differences were observed
in respiratory, cardiovascular, infectious, or neurologic complications between the
two groups. Other important endpoints such as transfer to an ICU, duration of
hospital stay, and overall mortality were not reduced with the use of routine
oximetry in a general care area in the subset of patients who recently underwent
cardiothoracic surgery. Now that pulse oximetry monitoring is so ingrained into the
perioperative setting, it is unlikely that we will see randomized outcome-based
studies with control groups that include patients with no oximetry monitoring.
The role of home oximetry in the preoperative evaluation of patients considering
surgery to predict postoperative complications has been explored. Hwang et al. [77]
used home oximetry to screen for potential sleep-disordered breathing in nearly 200
patients prior to elective surgery who had clinical evidence of OSA and used the 4%
ODI to see if this was predictive of postoperative complications. A significantly
higher rate of postoperative complications were seen in the 57% of the patients with
a 4% ODI >5/h (15.3% vs. 2.7%, P < 0.01) with an adjusted odds ratio of 7.2. Most
of the complications, however, were respiratory and simply required administration
of more supplemental oxygen and there were relatively few overall events.
Preemptive home oximetry in suspected OSA patients was not useful in predicting
hospital stay or other complications nor did it have any impact on major outcome
improvement.
382 H.R. Malish and P.C. Gay

Capnography

Since oximetry has not been shown to be a clear outcome benefit in perioperative
patients, it was natural to seek other monitoring modalities. End-tidal carbon
dioxide tension (ET-CO2) and transcutaneous carbon dioxide monitoring (tc-CO2)
accuracy have been compared in a sleep laboratory with PaCO2 levels in patients
wearing a nasal cannula or using nocturnal positive-pressure ventilatory assistance
[78]. ET-CO2 tension and tc-CO2 during diagnostic and therapeutic sleep studies did
not accurately reflect the simultaneous PaCO2 levels when PAP therapy was applied.
It is not surprising that ET-CO2 and tc-CO2 are utilized more for trend observations
as opposed to equivalent arterial PaCO2 levels.
Another investigation was undertaken in patients with and without OSA during
recovery from general anesthesia to compare the accuracy of oral guide nasal cannula
vs. sidestream capnometry and compared to an arterial PaCO2 values determined
simultaneously [79]. Mainstream capnometry was superior to sidestream capnom-
etry in both obese and nonobese patients. The study did not evaluate outcome
benefit or try to predict adverse consequences so the role for capnography as an
adjunct monitor to oximetry in postoperative patients remains unclear.

Management Algorithms

PACU

Optimal postoperative monitoring for the OSA patient must take into account the
surgery type and risk, patient characteristics, as well as anesthesia and analgesia-
specific factors. The 2006 ASA guidelines, directed by expert consensus in the
absence of good clinical evidence at the time, urged guidance of OSA patient dispo-
sition by a weighted scoring system and patient risk factors [30]. Perioperative risk
was broadly divided into severity and treatment of OSA, invasiveness of the surgery
and anesthesia used, and postoperative opioid requirements. The scoring system
was somewhat involved and did not take into account the importance of recurrent
PACU events in predicting more episodes of oxygen desaturation and increased
postoperative respiratory complications [41].
Taking into account 2006 ASA guidelines and recent evidence for identifying
patients most at risk for postoperative respiratory complications, Seet and Chung
[42] proposed an algorithm using recurrent PACU events as a predictive indicator to
guide postoperative disposition of the known or suspected OSA patient (Fig. 19.2).
A PACU event occurs if in one 30-min time block, the patient has any of the
following: (1) apnea for ³10 s (only one episode needed for yes), (2) bradypnea of
£8 bpm (three episodes needed for yes), (3) desaturations to <90% (three episodes
needed for yes), or (4) pain-sedation mismatch, as characterized by high pain scores
and high sedation levels observed simultaneously.
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 383

Prolonged stay in PACU

(> 30-60 min after modified Aldrete criteria met)

Known OSA Suspected OSA

(≥2 on STOP, 3 STOP-Bang)12

Non-compliant with PAP therapy‡, Recurrent PACU Respiratory Event (30-

Severe OSA (AHI > 30), or min block)#
Recurrent PACU Respiratory Event (30-min • Oxygen saturation <90% (3 episodes)
block)# • Bradypnea < 8 breaths/min (3 episodes)
• Oxygen saturation <90% (3 episodes) • Apnea ≥ 10 s (1 episodes)
• Bradypnea < 8 breaths /min (3 episodes) • Pain sedation mismatch
• Apnea ≥ 10 s (1 episodes)
• Pain sedation mismatch

No Yes Yes No

Moderate OSA (AHI > 16-30),

Postoperative parenteral or
oral opioids required
(> codeine 60 mg q4h, or
equivalent)

No Yes

Discharge to Postoperative Postoperative PAP Discharge to home if

home if care on the therapy‡ and care in a minor surgery or
minor surgical ward. monitored bed‡ with postoperative care on
surgery. continuous oximetry. the surgical ward.

Fig. 19.2 Postoperative management of the known or suspected OSA patient after general
anesthesia. Number of occurrence of more than one set of events in each 30-min evaluation period
while in the postanesthesia care unit (PACU), including repeat occurrence of the same event set.
‡PAP therapy may include continuous, bilevel, or autotitrating PAP. †Monitored bed – inpatient
area that would lend itself to early nursing intervention and includes continuous oximetry monitor-
ing (e.g., intensive care unit, step-down unit, or remote pulse oximetry with telemetry in surgical
ward) (adapted with kind permission from Springer Science + Business Media [42])

Recurrent PACU events occur when any one of the PACU respiratory events
occurs in two separate 30-min time blocks (not necessary to be the same event or
consecutive periods). Patients who are at high risk of OSA on the screening ques-
tionnaires and have recurrent PACU respiratory events are more likely to have post-
operative respiratory complications. It may be prudent to monitor these patients
postoperatively with continuous oximetry in an area where early medical interven-
tion can occur. The monitoring can occur in the step-down unit, on the surgical ward
near the nursing station, or with remote pulse oximetry with telemetry (Fig. 19.2).
384 H.R. Malish and P.C. Gay

Close postoperative monitoring would certainly be called for in patients with

known OSA with recurrent PACU events, but also in their absence if the patient’s
OSA is severe or if they are noncompliant (left side of Fig. 19.2). In the absence of
severe OSA, noncompliance, and recurrent PACU events, patients with moderate
OSA or requiring parenteral or higher dose oral opioids (codeine 60 mg every 4 h or
equivalent) may be managed postoperatively on the surgical ward with periodic
oximetry monitoring. It may also be expedient to place patients requiring postop-
erative parenteral opioids on supplemental oxygen [80]. The ultimate outcome
benefit of the interventions has yet to be demonstrated.
It is not difficult to imagine how the pulmonologist would be called to evaluate
either a known, suspect (or even previously unsuspected) OSA patient postopera-
tively for the aforementioned recurrent PACU events. For those with previously
undiagnosed but suspected OSA in the postoperative or medical inpatients setting,
our institution has developed an obstructive apnea systematic intervention strategy
(OASIS) protocol, as outlined in the top half of Fig. 19.3. PACU or overnight oxi-
metry, ABG, inpatient events, and discussion with the primary team are often
enough to guide initial decision making. Appropriate setting (outpatient vs. inpa-
tient) and timing (before or after discharge) of polysomnography can often be
difficult and will depend on local resources and lab availability.
Decision for attempted initiation of empiric PAP is also important, as indicated
by poor overnight or PACU oxygenation, coronary artery disease, congestive heart
failure, arrhythmia, or other reasons. In those for which an attempt at inpatient PAP
initiation is warranted, early assessment (prior to 4 p.m.) by the respiratory thera-
pist mask fit and patient willingness is recommended. Once PAP therapy continu-
ation is decided for in the context of the respiratory therapist’s assessment, close
follow-up is needed to assess patient tolerance. In the case of intolerance, reasons
must be assessed. In the case that PAP is tolerated, there is commonly room for fine
tuning and optimization until the patient undergoes a full polysomnography. This
imperative follow through of inpatient PAP initiation is outlined in the bottom half
of Fig. 19.3.
Known OSA patients who have been noncompliant with PAP therapy or have
severe OSA may have to be fitted with postoperative PAP therapy and cared for in a
monitored environment with continuous oximetry, particularly if there has been
recurrent PACU respiratory event. Known OSA patients previously on PAP therapy
should be encouraged to be compliant with PAP therapy postoperatively, and PAP
therapy should be ordered postoperatively, beginning in the PACU. Preliminary
studies have revealed that normalization of sleep architecture and AHI tends to be
delayed as far out as the seventh postoperative night [81]. Further outcome-based
research on the postoperative management of OSA patients is essential.
Disagreement exists as to whether OSA patients should be discharged for home
after surgery. The ASA guidelines highlighted that superficial surgeries or minor
orthopedic surgery using local or regional techniques and lithotripsy may be per-
formed on an ambulatory basis [30]. In our opinion, mild OSA patients (AHI 5–15),
who have undergone minor surgery without recurrent PACU respiratory events and
who do not require high doses of oral opioids for analgesia, may be discharged
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 385

Sleep consult submitted

Oximetry/ABG obtained

Call requesting service

What’s the issue?
Previous evaluation?
Discharge pending?
Patient refusing CPAP?

Follow-up as outpatient: Perform consultation: based

Sleep lab or home study on oximetry, comorbidities,
convenience (eg, paraplegic)

Sleep lab follow-up: Begin empirical CPAP/BPAP*: Polysomnogram now: either

Outpatient return visit Unit: start BPAP portable in-hospital (because
scheduled Ward: CPAP, continue BPAP of medical issues) or in sleep
lab (bed availability)

* Criteria Contact respiratory therapy

1. Bad overnight oxygenation
• 4% desaturation index > 20
• Saturation ≤ 75% or New CPAP introduction?
• Mean saturation ≤ 88% or Auto-adjusting PAP
• Saturation ≤ 90% ≥ 15% of study • Introduction: before 4 pm
2. Or coronary artery disease+ • Fit with mask and pillows
3. Or congestive heart failure + • Assess patient’s willingness
4. Or arrhythmia
5. Or reason to delay PSG
Respiratory therapy
contacts sleep service

Patient agrees Patient intolerent

APAP (min/max 4/20 cm H 2O) RT records why?

• Heated humidification • Mask discomfort
• Repeat oximetry on APAP • Pressure
• If initial oximetry on O then APAP on O • Claustrophobia
2 2
• If initial oximetry on room ari, then APAP alone • Refusal
BPAP for P aCO2> 50 mm Hg or pH < 7.35
Heated humidification (1 or 2 setting)
Oxygen decided as above
Settings per ICU or previous use
Download
APAP and
oximetry
Continue CPAP/BPAP Patient non-adherent Sleep Service contacts
• Order standard fixed or refuses to continus: primary service:
CPAP, set at > 95% • Why? • Recommend bed elevation
time pressure off and avoid back position
• Download data
• Minimize narcotics,
sedatives
• Follow-up scheduled in
sleep lab
Discharge from hospital
Supplemental oxygen

Follow-up PSG scheduled Continue CPAP (prescription given)

(No home CPAP) with follow-up PSG scheduled in sleep lab

ABG = arterial blood gas. CPAP = continuous PAP. BPAP = bi-level PAP. PSG = polysomnography.
APAP = auto-adjusting PAP. PSG =polysomnography. RT = respiratory therapy.

Fig. 19.3 Obstructive apnea systematic intervention strategy (OASIS) for assessing postoperative
or medical patients for sleep-disordered breathing, with follow-through management algorithm
based on patients’ PAP willingness. ABG Arterial blood gas; CPAP continuous PAP; BPAP bi-level
PAP; PSG polysomnography; APAP auto-adjusting PAP; PSG polysomnography; RT respiratory
therapy (adapted from [22])
386 H.R. Malish and P.C. Gay

home at the discretion of the attending physicians (Fig. 19.2). Ambulatory surgical
centers managing OSA patients should have transfer agreements to inpatient
facilities and should be equipped to manage contingencies associated with OSA.

Intervention Protocols

General Surgery

Despite a paucity of data, interest remains high in improving outcomes in those with
known or suspected sleep-disordered breathing through preemptive or protocol-
directed PAP therapy. By reviewing three cases, Bolden et al. [82] illustrate issues
in OSA patients that occurred prior to and after implementation of an OSA protocol.
When CPAP was becoming increasingly available in the early 1990s, one hospital
mandated a protocol to treat all postoperative patients with CPAP. This came in
response to a postoperative death in an OSA patient in which CPAP was withheld,
shortly followed by rescue of a postoperative patient from serious complications
after treating with CPAP [83]. Of the subsequent 14 patients, in which CPAP was
given preoperatively and for 24–48 h postextubation with all subsequent sleep, none
developed major respiratory complications. Though the data was limited, the authors
advocated for increased awareness of OSA patients and argued for CPAP before and
after surgery.

Intervention Protocols in Orthopedic Surgery

In one prospective study, high-risk OSA patients planning to have orthopedic surgery
were identified by using the SACS score. Patients were then randomized to receive
routine postoperative care either with or without autotitrating PAP. They aimed to
determine the accuracy of the SACS score in predicting whether high-risk OSA
patients would have postoperative sleep-related desaturations or a respiratory distur-
bance index >15, and the benefit they may gain from anticipatory CPAP therapy
[45]. Of 42 patients enrolled, 9 were observed as low risk, while the remaining 33
underwent randomization after being deemed high risk for OSA. The SACS score
was found to be 85% sensitive in detecting those with a postoperative respiratory
disturbance index ³15. While their lower risk counterparts were not immune to
significant oxyhemoglobin desaturation or respiratory events on their first postop-
erative night, events were less severe than for those in the high-risk group.
Interestingly, patients spend less time at or above 90% oxygen saturation on the
night prior to discharge (most often postoperative day 4) in comparison to the night
immediately following surgery. As discharge approaches, patients are often taken
off empiric supplemental oxygen and continuous monitoring, making lending the
OSA patient more susceptible to REM rebound postoperative day 3 and beyond.
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 387

Preemptive CPAP use did not significantly affect outcomes when used in patients
with high clinical suspicion for OSA. The lack of difference was thought due to
more than half of the patients’ lack of compliance with and intolerance of PAP,
often in the setting of substantial postoperative pain.

Intervention Protocols in Gastric Bypass Surgery Patients

Special consideration of the morbidly obese patient for harboring perioperative risk
has been discussed. Aside from sleep-disordered breathing, respiratory risk also
extends to atelectasis, abnormal gas exchange, and impaired clearance of secretions.
A multicentered observational study prospectively evaluated major adverse out-
comes at 30 days in patients undergoing bariatric surgery at ten sites within the
United States [84]. Diagnosis of OSA, impaired functional status, and history of
deep vein thrombosis or pulmonary embolus were factors independently associated
with an increased risk of the composite end point.
Although continuous and bi-level PAP effectively treat these problems, postgas-
tric bypass PAP therapy has not been universally adopted out of concern that posi-
tive pressure can cause anastomotic leaks by way of massive bowel wall distention
[85]. Opponents of PAP therapy in this setting report no differences in outcomes
when comparing known OSA patients who were using preoperative PAP therapy or
not, as well as those with no known OSA [86]. The majority of patients in that
review (811) were without known OSA, followed by 144 PAP-dependent and 140
non-PAP dependent patients with known OSA. In the absence of any reported anas-
tomotic leaks or deaths, 1, 3, and 6 pulmonary complications were noted in the PAP
dependent OSA, non-PAP OSA, and no known OSA groups, respectively.
The majority of practicing pulmonologists would have difficulty withholding
postoperative PAP therapy from those who clearly need it on the basis of decreasing
risk of possibly overexaggerated pressurized air complications. To assess the safety
and efficacy of postoperative PAP after Roux-en-Y gastric bypass, one study pro-
spectively evaluated risk of subsequent anastomotic leaks and pulmonary complica-
tions [87]. Of the 1,067 patients included, 420 had known OSA, only 159 of which
were using CPAP. While no episodes of pneumonia were diagnosed in any of the
patients, only 2 of the 15 major anastomotic leaks occurred in patients treated with
CPAP, and there was no correlation found between the two (P = 0.6). There is some
evidence that bi-level PAP therapy improves pulmonary function after open Roux-
en-Y gastric bypass, based on a small single-center prospective study [88]. Baseline
pulmonary function tests were performed on 27 patients, who were randomized to
then receive either conventional postoperative care or bi-level PAP. Preoperative
expiratory flow reduction found in both groups was not statistically significant
between the groups. In the group receiving bi-level PAP therapy, forced vital capacity,
FEV1, and oxygen saturation were significantly higher in comparison to the control
group. Despite these findings, bi-level PAP did not translate into shorter length of
stay or improved complication rates.
388 H.R. Malish and P.C. Gay

Conclusion

The role of “just-in-time” or perioperative PAP therapy intervention and effect on

outcomes has yet to be determined. Emphasis has been placed on preoperative
screening for suspect OSA and minimizing risk for known and suspect OSA patients
perioperatively. Our institution his implemented in-hospital sleep consultative ser-
vices in combination with OASISwith a close follow through protocol to aid workup
and initial management of perioperative inpatients with suspected OSA. Many
hospitals throughout the country have adopted their own approaches in screening
and monitoring suspect and known OSA patients perioperatively. As long as periop-
erative outcomes in this population varies by institution, perioperative outcomes in
OSA patients will likely be a future element for judging best practice performance.
In the absence of robust prospective outcomes data to guide us in the monitoring
and postoperative management of OSA patients undergoing surgery, we must continue
to develop best practices to avoid situations that we do not realize are dangerous [89]
so that we do not end up involved with what has become known as the prototypical
OSA postoperative malpractice case. But how do we know that the prototypical case
involves severe OSA, morbid obesity, abdominal incision, narcotics, extubation with-
out CPAP or supplemental oxygen, an unmonitored setting, and a relatively isolated
ward room? Unexpected sudden death registries such as the ASA Closed Claims
Project have helped. The project’s purpose is to identify major areas of loss in anes-
thesia, patterns of injury, and strategies for prevention. By combining preoperative
screening, perioperative optimization, and identification of recurrent postoperative
and PACU events, optimal risk identification, prevention, and intervention will
hopefully be achieved as we pursue more robust prospective outcomes data.

Summary of Keypoints

• Perioperative complications occur more commonly in those with OSA and can
have significant impact on patient outcomes.
• Early identification of patients with OSA may forewarn the clinician of potential
difficulty with airway maintenance intra- and postoperatively, perhaps influenc-
ing choice of anesthetic technique and postoperative monitoring environment.
• In the last several years, questionnaires have been developed with validation in
the preoperative setting.
• When additional factors were included, the STOP-Bang Questionnaire had the
highest sensitivity, especially for patients with moderate to severe OSA.
• Algorithms developed to minimize perioperative risk in those with known or
suspected OSA take into account the patients’ risk of suspected OSA, severity of
known OSA, type of surgery, comorbidities, and changes in OSA status.
• Perioperative OSA precautions may include anticipating possible difficult airway
experiences, the use of short-acting anesthetics agents, opioid minimization, full
19 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 389

reversal of neuromuscular blockade verified prior to extubation, and extubation

in a nonsupine position.
• A multimodal approach to minimize postoperative opioids may include periph-
eral nerve block catheters or neuro-axial catheters dispensing local anesthetic
agents, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, acetaminophen,
pregabalin, tramadol, dexamethasone, ketamine, clonidine, gabapentin, or the
nonopioid sedative dexmedetomidine.
• Taking into account 2006 ASA guidelines and recent evidence for identifying
patients most at risk for postoperative respiratory complications, we advocate an
algorithm using recurrent PACU events as a predictive indicator to guide postop-
erative disposition of the known or suspected OSA patient.
• For those with previously undiagnosed but suspected OSA in the postoperative
or medical inpatients setting, our institution has developed an OASIS protocol.
• Follow through is imperative for attempted initiation of empiric PAP, as indi-
cated by poor overnight or PACU oxygenation, coronary artery disease, conges-
tive heart failure, or arrhythmia, among others.
• While sustained high interest has driven preemptive or protocol-directed PAP
therapy as we discuss in the context of general surgery, orthopedic surgery, and
gastric bypass surgery patients, the role of “just in time” or perioperative PAP
therapy intervention and effect on outcomes has yet to be determined.
• Perioperative OSA outcomes are a ripe target for best practice performance, as
are missed prototypical OSA postoperative mortalities ripe targets for malpractice
claims.

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1997;85:452–60.
Chapter 20
Sleep and Critical Illness

Nimesh Patel and Sairam Parthasarathy

Keywords Sleep • Critical illness • Mechanical ventilation • Artificial respiration

• Noise • Intensive care unit

Introduction

Sleep is vital for health and well being and involves a complex set of neuro-
physiological processes [1]. A complex set of derangements characterize critical
illness, and involve almost every organ system, including the neurological
system. It follows that when these two spheres of complexity meet, i.e., the study
of sleep during critical illness assumes an even higher level of complexity. Despite
such hurdles, the potential rewards to better understanding sleep during critical
illness have immense bearing to both sleep medicine and critical care fields [2].
While the field of sleep medicine needs further mechanistic data to determine the
effect of sleep on survival, existing evidence suggests that sleep disturbances exert
deleterious effects on patients with critical illness. Therefore, the focus of this
chapter is to provide the reasons as to why, and what, a pulmonologist needs to know
about sleep and critical illness.

N. Patel
Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine,
University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA
S. Parthasarathy (*)
Research Service Line, Southern Arizona VA Health Care System, 3601 S. Sixth Avenue,
Mai Stop 0-151, Tucson, AZ 85723, USA
e-mail: [email protected]

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 395
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8_20,
© Springer Science+Business Media, LLC 2012
396 N. Patel and S. Parthasarathy

Why Care?

Why should a pulmonary and critical care specialist care about sleep during critical
illness? Emerging evidence supports the notion that severe sleep derangements
during critical illness may influence the outcome and the perception of patients
regarding their care. Specifically, inability to sleep due to high noise levels is among
the top complaints of hospitalized patients [3]. When survivors of critical illness
were asked to rate their sleep quality, subjects reported worse sleep quality in the
intensive care unit (ICU) when compared to that at home [4]. The subjective nature
of such reports do not detract from the study findings, in that, the reduction in
perceived patient satisfaction is central to patient-centered care [3]. Therefore,
reduction of noise levels is an important consideration in guiding design and construction
of hospital facilities [3].
Sleep disturbances are associated with many objective adverse effects. For
instance, a small prospective observational cohort of patients (n = 24) who suffered
blunt head injury, sleep-wakefulness organizational patterns in the sub-acute stages
of post-traumatic coma was associated with survival and functional recovery [5].
In this study, organized sleep patterns – i.e., sleep organized into well-recognizable
non-rapid eye movement (NREM) and REM sleep that were alternating with each
other – was associated with better outcome (OR 10.8; P = 0.01). In the same
study, the 24 h polysomnography-derived sleep-wakefulness organizational state or
lack thereof was more predictive of outcome than neuro-radiological findings, age,
or Glasgow coma scale. However, these studies offer interesting preliminary obser-
vations that require validation in large, controlled longitudinal studies [5].
In another prospective observational cohort, the proportion of patients with
abnormal sleep in patients who failed a trial of non-invasive ventilation was greater
than in those who were successfully treated [6]. Moreover, in this study, patients
failing non-invasive ventilation had worse sleep quality with greater circadian
sleep-cycle disruption and less nocturnal REM sleep than those who were
successfully treated with non-invasive ventilation [6]. Moreover, in a study of
medically ill patients receiving mechanical ventilation, Watson and colleagues dem-
onstrated that burst-suppression in EEG – derived from automated bispectral index
(BIS) monitoring – was associated with greater mortality (hazard ratio, 2.04; 95%
confidence interval, 1.12–3.70). However, polysomnography was not conducted in
this study. Although such a body of data is accumulating with regards to the
relationship between EEG-derived brain states and patient outcomes, as in all
observational studies, whether such sleep-wakefulness or altered brain states play a
causative role or are mere associates is less clear [2].
The effect of sleep deprivation on survival has been demonstrated in several animal
studies. [7]. Specifically, in a cecal ligation and puncture model of sepsis, mice that
were subjected to sleep deprivation were more likely to die than mice in the control
group [7]. Moreover, in another sepsis model, administration of dexmedetomidine –
a sedative known to promote true endogenous sleep – was associated with reduction
in inflammation and mortality rate [8]. However, sleep or EEG-derived brain states
were not measured in this study [8]. There is preliminary evidence that sleep
20 Sleep and Critical Illness 397

fragmentation may contribute to increased mortality in humans who are hospitalized

for a critical illness [9]. However, more definitive intervention-based studies need
to be performed in order to confirm a causal role of sleep disruption in mortality due to
critical illness.

Measurement of Sleep During Critical Illness

Several excellent reviews summarize the extent and effect of sleep disturbances on
outcome in critically ill patients [10–13]. For example, sleep derangements are more
pronounced in critically ill patients receiving mechanical ventilation, as compared
to ambulatory patients; however, there is large variability in the nature and severity
of sleep derangements reported [10]. For example, some investigators have reported
that such patients spend 50% of the recording time in a 24 h period in slow wave
sleep, whereas others have observed little (3–9%) or no slow wave sleep in critically
ill patients [14–17]. Such large variability in the assessment of sleep in critically ill
patients may, in part, be due to difficulty analyzing EEG, secondary to the con-
founding effects of sedative medications, underlying illnesses such as sepsis, and
measurement artifacts in the ICU environment [18]. Therefore, automated methods,
such a EEG spectral analysis, may be more reliable than manual methods using
traditional scoring criteria in critically ill patients receiving mechanical ventilation
[19]. However, automated methods do not capture pathological wakefulness
states – wherein the patient is behaviorally awake but displays a sleep EEG pattern
[6]. Video-assisted polysomnography may allow the distinction of such pathological
wakefulness states; however, the reproducibility of assessing the behavioral states
of critically ill patients is as yet unknown [2]. Nevertheless, there is a dire need for
standardized and validated means of assessing the brain states of critically ill
patients, and to link the findings to tangible patient outcomes.
Other methods of assessing sleep in the ICU include behavioral assessment,
questionnaires, and Actigraphy [20, 21]. In a small observational study, actigraphy
and behavioral assessment by the nurse were found to be inaccurate and unreliable
methods to monitor sleep in critically ill patients [21]. Similarly, in an intervention-
based study involving melatonin, Bourne et al. found that sleep efficiency inferred
from BIS was not correlated with actigraphy or nurse assessment of sleep [22].
In this study by Bourne et al., a threshold BIS score of less than 80 was used to infer
sleep; however, such a threshold was previously identified to indicate onset of sleep
in healthy volunteers and was not validated in critically ill patients [23]. In contrast,
other investigators found good correlation between quiet periods measured by
actigraphy and sleep time estimated by nurses [24]. But, these investigators did
not measure sleep using EEG [24]. A comprehensive review of various sleep
measurement methods used to study sleep during critical illness were compared
and the pros and cons of various methodologies – that included conventional poly-
somnography, BIS, actigraphy, nurse and patient self-assessment – were critically
assessed [25]. Patient sleep self-tools that were reviewed included the Verran/
Snyder-Halpern Sleep Scale, Hospital Anxiety and Depression Scale, sleep in the
398 N. Patel and S. Parthasarathy

ICU questionnaire, and Richards-Campbell sleep questionnaire [25]. This critical

review concluded that polysomnography was still considered the gold-standard
but suffered from feasibility concerns, whereas patient self-reports were limited
by patient misperception and impaired cognitive state [25]. Nurse assessment of
critically ill patients’ sleep was both labor-intensive and unreliable.
In summary, research studies of sleep during critical illness in patients receiving
mechanical ventilation should include EEG-based assessment of sleep with con-
comitant video recordings. Analysis of EEG may involve spectral analysis, sleep-
wakefulness organizational state or R&K methodology (REM sleep features), and
delineation of pathological or dissociative sleep states using simultaneous video
recordings [6, 18]. Reliable clinical tools for measurement of sleep during mechanical
ventilation in critically ill patients are currently not available. Whereas, in spontane-
ously breathing and cognitively intact patients residing in the ICU, subjective sleep
assessment tools may be feasible but are prone to patient misperception.

Nature and Extent of Sleep Disturbances

The ICU environment promotes sleep derangements. However, it is uncertain

whether critically ill patients suffer from sleep deprivation. Some investigators have
reported adequate sleep time (7–10 h/day) in critically ill patients [13, 14, 26].
However, others have reported reduced sleep times (3–6 h/day) [27]. Nevertheless,
even in the studies that reported “adequate” average sleep times, there was wide
variation in amount of total sleep time ranging from 2 to 19 h over a 24 h period
[14]. Therefore, sleep deprivation is common in critically ill patients; however,
other factors such as amount of sedatives, acuity of illness, and level of analgesia
may be playing confounding roles.
Sleep fragmentation is another potential cause of sleep derangement in the ICU.
[16]. Sleep fragmentation, measured as the sum of arousals and awakenings, show
wide inter-patient variability. In some studies, sleep fragmentation as high as 63/h
have been noted and in others sleep fragmentation was found to be much lower
(13/h) [17, 26]. Such differences may be attributable to difference in sedation targets
and practices. For example, in the study involving continuous sedation and paralysis,
the sleep fragmentation measures were as expected much lower [17].
Decreased REM sleep is a consistent finding in critically ill patients [10].
Medications such as benzodiazepines, narcotic analgesics, critical illness, or mode
of ventilation may be responsible for the paucity of REM sleep in this population [6,
13, 15, 17, 28]. Slow wave sleep was noted to be increased in some investigators,
but this may have been due to the heavy sedation employed in such patients who
were receiving non-depolarizing muscle paralytics [17]. Most other studies have
demonstrated a paucity of slow wave sleep [10, 12].
Atypical patterns of sleep have been observed in critically ill patients who are
receiving mechanical ventilation [13]. Cooper et al. categorized such patients as not
having EEG characteristics of stage 2 (now N2) NREM sleep – such as K complexes
20 Sleep and Critical Illness 399

and spindles [13]. Some of these patients were noted to have brain states of pathologic
wakefulness – characterized by behavioral correlates of wakefulness (saccadic eye
movements and sustained electromyogram (EMG) activities) coinciding with EEG
features of slow wave sleep which is not seen during wakefulness. Other groups have
reported such states with video-recording based observations that are compatible
with “abnormal” wakefulness, whilst the EEG is demonstrative of sleep [6]. Roche-
Campo et al. went a step further by interacting with these patients to assess their
responsiveness and assess the EEG-response to eye opening and closing.
Circadian rhythm is also abnormal in critically ill patients. The amplitude of
circadian – measured as fluctuation in urinary metabolite of melatonin every 4 h – was
markedly lower in septic critically ill patients when compared to non-septic criti-
cally ill patients or healthy controls [29]. Other investigators have studied circadian
rhythms in critically ill patients by measuring serum and/or urinary melatonin levels
that suggested that a majority of medically critically ill patients lacked circadian
rhythms [30]. Critically ill patients with brain injury may have a greater depression of
the amplitude of their circadian pattern as measured by serum melatonin and corti-
sol levels than medically ill patients in the ICU [31, 32]. Other methods of measuring
circadian rhythm, such as sleep and temperature nadirs have revealed a lack of circadian
rhythm in medical and post-operative critically ill patients [13, 33].

Causes and Cures

Numerous causes for sleep derangements during critical illness exist (Table 20.1).
Environmental influences (such as noise, provider interactions, and light), medica-
tions, mechanical ventilation, pain, acuity of underlying illness and other factors
including co-existing medical illnesses may all contribute to sleep derangements
during critical illness. Each of the causes of sleep derangement will be discussed in
the context of potential cures.

Table 20.1 Causes of sleep disruption in critically ill patients

Mechanical ventilation
Mode of ventilation
Level of ventilator assistance
Patient-ventilator dyssynchrony (Non-triggering and central apneas)
Environment
Noise
Lighta
Temperaturea
Patient care activities
Medications
Acuity of illness
a
More evidence is needed.
400 N. Patel and S. Parthasarathy

The ICU is generally a noisy environment with noise levels ranging from
50–75 dB with peaks upwards of 90 dB [10]. Such noise levels far exceed the night-
time noise levels recommended by the WHO [34]. Nearly 21% of the sleep frag-
mentation episodes were attributable to spikes in noise level by Gabor et al. [27].
Application of mixed frequency white noise in a simulated ICU noise environment
can reduce sleep fragmentation in healthy volunteers, but a similar study has not
been performed in critically ill patients [35]. Other methods to reduce noise levels
would be providing single rooms with sound insulation, education of care providers,
and installing visual noise displays in the ICU room to alert or make care providers
aware of the noisy environment in an effort to reduce noise levels [27, 36].
Visits by healthcare providers may be associated with noise or touch, i.e., care
giving – in the form of physical therapy, bath, checking vital signs, repositioning, or
treatment administration by nurse or respiratory therapist. Limiting or coordinating
such care may reduce the number of interruptions but this has not been studied as a
sleep-promoting intervention in critically ill patients. In hospitalized non-critically
ill patients, a program designed to minimize nighttime awakenings of patients was
associated with a reduction is nighttime sedative use [37]. In critically ill mechani-
cally ventilated patients, Gabor et al. observed that such interaction with healthcare
providers, as recorded on the video-polysomnography, accounted for 10% of the
sleep fragmentation episodes. Other ICU environmental effects such as light
and temperature may be influencing sleep in critically ill patients, but these have
not been critically studied using intervention-based approaches. Conceivably, the
derangements in circadian rhythm observed during critical illness may be attributable
to the well-lit ICU environment – with light being the most powerful zeitgeber
(“time giver” in German). However, this conclusion requires studying the effect of
light-based intervention on sleep in the ICU environment.
A body of literature has been evolving in the study of the effect of mechanical
ventilation on sleep during critical illness. A significant proportion (about 40%) of
patients in the ICU requires mechanical ventilation, and studies have demonstrated
significant sleep derangements in such patients as delineated earlier in this chapter.
However, not all of the sleep derangements in such patients may be due to mechanical
ventilation per se – because, attendant factors such as nasogastric tubes, restraints,
sedative and analgesic medications, frequent suctioning, and mouth guards may be
in part responsible for discomfort and consequent sleep disruption. A rigorous
way of evaluating the effect of mechanical ventilation on sleep quality may be to
randomly assign patients to different modes or level of mechanical ventilation and
even perform cross-over studies in order to minimize the effects of the known inter-
patient variability in sleep quality.
In a cross-over, randomized, controlled study, assist control ventilation was associ-
ated with reduction in sleep fragmentation when compared to pressure support mode
[16]. The worsening of sleep fragmentation during pressure support was noted to be
due to the appearance of central apneas – which when ameliorated by the adminis-
tration of deadspace – was associated with improved sleep efficiency and reduction
of sleep fragmentation [16]. Interestingly, patients with heart failure were more
likely to develop such central apneas while receiving pressure support ventilation.
20 Sleep and Critical Illness 401

Considering that the magnitude of pressure assist administered during pressure

support ventilation may have bearing on the appearance of central apneas and conse-
quent sleep disturbance. Fanfulla et al. have compared pressure support that was
titrated by measuring transdiaphragmatic pressure (physiological) vs. clinically
determined (usual) pressure support [38]. Physiological level of pressure support was
achieved by reducing measured transdiaphragmatic pressure by 40–80% of that
during spontaneous unassisted breathing and usual (clinically determined) pressure
support was that which reduced PaCO2 by at least 5%. The investigators found that
physiologically titrated pressure support was associated with better sleep efficiency,
greater proportion of time spent in REM sleep, and such improvements in sleep were
correlated with levels of ventilator non-triggering [38]. In this study, 3 of 9 (33%) of
the patients manifested central apneas (5–33 events/h) during usual pressure support
and the magnitude of central apneas were inversely correlated with the amount of
REM sleep [38]. Toublanc et al. compared low levels of pressure support vs. assist
control ventilation in a randomized controlled study with cross-over design involving
patients with acute on chronic respiratory failure [39]. In this study, both objective
and subjective sleep quality were better during assist-control when compared to pres-
sure support ventilation. However, the investigators did not find central apneas which
may be explained by the low levels of pressure support (6 cm H2O) and in that the
majority of patients suffered from obstructive lung disease – which is expected to
dampen the loop gain and decrease the risk for central apneas [40]. Yet another study
compared three modes of ventilation – assist-control, automatically adjusted pres-
sure support, and clinically adjusted pressure support – and found no effect of mode
of ventilation on sleep quality [41]. In this study, pressure support was adjusted clini-
cally (i.e., to keep respiratory rate less than 35 breaths/min and tidal volume at
6–8 mL/kg predicted body weight) or through a closed-loop knowledge-based sys-
tem that maintains pressure assist at a level that avoids hypo- and hyperventilation.
In sum, these studies underscore the need for optimal adjustment of pressure
assist in pressure support, with a lack of such need during assist-control ventilation.
The clinical implications of such findings are that the clinician needs to be knowl-
edgeable of the pitfalls of the mode and level of ventilator assistance. While assist-
control mode of ventilation is forgiving, pressure support mode requires careful and
constant titration making it more labor- and knowledge-intensive to ensure adequate
sleep during mechanical ventilation.
Medications may influence sleep during critical illness. Benzodiazepines, narcotic
analgesics, and propofol are commonly used sedatives in critically ill patients.
Benzodiazepines decrease the time needed to fall asleep, decrease awakenings,
increase sleep duration, and increase sleep efficiency but, they also increase the
number of spindles, increase cortical EEG frequency (at low doses), decrease EEG
amplitude and frequency (at high doses), and suppress REM and slow wave sleep.
Although, the clinical importance of these EEG alterations is not clear, an ideal
hypnotic should preserve normal sleep pattern. Narcotic analgesics also suppress
REM sleep, cause a dose-dependent slowing of EEG, and suppress slow wave
sleep [28]. In sum, a medicated state may resemble sleep on the surface, but may not
provide the physiological benefits associated with true sleep.
402 N. Patel and S. Parthasarathy

Discontinuation of medications may also influence sleep in critically ill patients.

Specifically, discontinuation of opiates can cause rebound of REM sleep in
post-operative patients and lead to a resurgence of nightmares or hypoventilation
accompanied by hypoxia in the post-operative patient [28]. Administration of
norepinephrine or epinephrine can reduce REM and slow wave sleep, whereas
corticosteroids can cause nightmares and reduction in REM sleep [42].
Unlike conventional sedative agents, dexmedetomidine (a centrally acting a2-
adrenergic agent) promotes sleep through central sleep neuronal pathways [43].
Such promotion of endogenous sleep may be preferable, but there are no published
studies evaluating polysomnography during dexmedetomidine administration.
Besides medications, multi-component approaches to improving sleep through
reduction of sedative need and reduction of environmental stimuli have been
achieved by Inouye et al. [44]. However, in this study sleep quality was not mea-
sured in an objective fashion. The measures taken to minimize sleep disturbances in
the elderly patients included unit-wide noise-reduction strategies (e.g., quiet hallways,
vibrating beepers, and silent pill crushers) and consolidation of care delivery
interruptions (e.g., vital signs, procedures, and rescheduling of medications) [44].
However, adherence to such sleep promotion measures was difficult in comparison
to other aspects of this multi-component approach (such as mobilization).

Conclusion

In conclusion, sleep derangements are quite severe in critically ill patients. In

critically ill patients, mechanical ventilation, medications, environmental noise,
and care giving can impact sleep quality. Many tangible outcomes such as poor
neurological outcome in head trauma, non-invasive ventilation failure, delirium
may be determined or associated with sleep during critical illness. However, inter-
vention-based trials are needed to ascertain the relationship between these factors
and sleep as well as identify and implement effective means for improving sleep
in such patients.

Summary of Keypoints

• Sleep disturbances are severe during critical illness.

• Mechanical ventilation, noise, patient-care activities influence sleep.
• Delirium, non-invasive ventilation failure, poor neurological outcomes are
associated with sleep disturbances during critical illness.
• Improving sleep in critically ill patients is patient-centered care and good
medicine.
20 Sleep and Critical Illness 403

Acknowledgment Dr. Parthasarathy was a recipient of an NIH/NHLBI grant (HL095748) during

the writing of this manuscript.

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20 Sleep and Critical Illness 405

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Index

A Apnea–hypopnea index (AHI), 94, 260

Acetazolamide, 231, 264 Armodafinil, 41–42, 294
Actigraphy, 249–250, 292, 407 Arrhythmias, 128
Acute insomnia, 243 Asthma, 240
Acute mountain sickness (AMS) airway narrowing, 212–213
acetazolamide, 264 diagnosis, 213
incidence, 263 DIMS and EDS, 259
medications, 265 pathogenesis, 212
oral steroids, 266 population based study, 240–241
Adaptive servo-ventilation (ASV), 231, 232 sleep disturbances, 213
Adrenocorticotrophic hormone, 10 ASV. See Adaptive servo-ventilation (ASV)
Advanced sleep phase disorder (ASPD) Atrial fibrillation, 149
diagnosis, 288–289 Autotitrating positive airway
treatment, 289 pressure (APAP), 68–69, 152
Agomelatine, 36–37
Airway reconstructive surgery, 181
Allergic rhinitis, 185–186 B
Almitrine, 211, 266 Benzodiazepine receptor agonists
Almorexant, 36 (BZRAs), 267
American Academy of Sleep Medicine Benzodiazepines
(AASM), 66, 95, 166, 287 hang over effects, 19
American Society of Anesthesiologists’ high altitude sickness and insomnia,
(ASA) checklist, 384 264–265
American Thoracic Society, 137, 141 insomnia, 18
Antidepressants, 35 pharmacokinetics and dosing, 20
insomnia Berlin questionnaire, 384
doxepin, 274 Bilevel positive airway pressure (BPAP), 217
trazodone, 274–275 Blood pressure, 148–149
sleep-promoting drugs Bronchospastic airway disorders, 259
bupropion, 35 Bupropion, 35
mirtazapine, 35
monoamine oxidase inhibitors, 35
SSRI and SNRI, 32–34 C
trazodone, 31–32 Capnography, 392
tricyclic antidepressants, 32 Carbonic anhydrase inhibitors, 264
Antihistamines, 35 Cardiac arrhythmias, 149–150

M.S. Badr (ed.), Essentials of Sleep Medicine: An Approach for Clinical Pulmonology, 407
Respiratory Medicine, DOI 10.1007/978-1-60761-735-8,
© Springer Science+Business Media, LLC 2012
408 Index

Catathrenia, 346–347 delayed sleep phase disorder

Centers for Medicare and Medicaid diagnosis, 286
Services (CMS), 211 treatment, 286–288
Central nervous system, 79 free-running type
Central sleep apnea (CSA) diagnosis, 289–290
breathing instability, 225 treatment, 290
clinical features and diagnosis, 229–230 irregular sleep–wake rhythm
clinical syndromes, 232 diagnosis, 290–291
hypocapnia, 223–224 treatment, 291
management jet lag
pharmacologic therapy, 231–232 diagnosis, 294
positive pressure therapy, 230–231 treatment, 294–295
supplemental O2 and CO2, 232 shift work disorder
pathophysiologic classification diagnosis, 292
hyperventilation, 227 treatment, 292–294
hypoventilation, 226 Cognitive-behavioral therapy (CBT),
risk factors 154, 275
age and gender, 228 Confusional arousal
medical conditions, 228–229 clinical symptomatology, 326
sleep state, 227–228 definition, 325
Chest wall disorders diagnostic workup, 326
diagnosis, 215 epidemiology, 326
pathophysiology of hypoxemia, 214–215 etiology, 326
therapy, 215 pathophysiology, 326
Cheyne–Stokes respiration, 224, 225, 232 treatment, 327
Chronic obstructive pulmonary disease Congenital central hypoventilation syndrome
(COPD) (CCHS), 226
hypoventilation Continuous positive airway pressure (CPAP),
measurement, 209 68, 395, 396
rapid eye movement, 208, 209 adherence, 154
hypoxemia adverse effects, 151
clinical consequences, 209–210 beneficial effects
diagnosis, 210 blood pressure, 148–149
treatment, 210–211 cardiac arrhythmias, 149–150
medications, 211–212 excessive daytime sleepiness, 148
neuromuscular disorders, 212 glucose metabolism, 150–151
noninvasive positive pressure heart failure, 149
ventilation, 212 motor vehicle accidents, 151
obstructive sleep apnea, 212 neurocognitive function, 150
respiratory dysfunction, 209 pulmonary hypertension, 149
Circadian disorders central sleep apnea, 230–231
advanced sleep phase disorder, 288–289 vs. MAS, 164–165
biology mechanisms, 147–148
light and melatonin, 284 modifications, 153–154
SCN neurons, 283 objective compliance monitoring, 174
delayed sleep phase disorder, 285–288 titration
free-running type, 289–290 auto titration, 152–153
irregular sleep–wake rhythm, 290–291 predictive equations and and
jet lag, 294–295 bedpartner, 153
shift work disorder, 291–294 treatment, indication, 166
Circadian rhythm sleep disorders (CRSD) COPD. See Chronic obstructive pulmonary
advanced sleep phase disorder disease (COPD)
diagnosis, 288–289 Coronary artery disease, 127
treatment, 289 CSA. See Central sleep apnea (CSA)
Index 409

D Excessive daytime sleepiness (EDS), 60, 259

Daytime sleepiness continuous positive airway pressure, 148
CNS pathology, 79 differential diagnosis, 83, 84
demographic factors, 78–79 sodium oxybate and modalnil, 44
differential diagnosis symptomatic treatment, 295
idiopathic hypersomnia, 85 systematic approach, 85
narcolepsy, 83 Excessive sleepiness
OSAHS, 83 alcohol risk, 140
restless leg syndrome, 84–85 direct and functional outcomes, 131
sleep–wake cycle, 85 Expansion sphincter pharyngoplasty (ESP),
Epworth sleepiness scale, 81–83 192, 195
maintenance of wakefulness test, Exploding head syndrome (EHS), 346
80–81
measurements, 83
medications, 77 F
multiple sleep latency test, 79–80 Fall asleep accidents, 131
sleep factors, 76–77 Fatigue Severity Scale (FSS) scores, 260
systematic approach, 85–87 Food and Drug Administration (FDA), 267
Delayed sleep phase disorder (DSPD) Free-running type
diagnosis, 286 diagnosis, 289–290
treatment, 286–288 treatment, 290
Diabetes, 79, 128–129 Full-night polysomnography, 94
Difficulty initiating or maintaining sleep Full wakefulness, 1
(DIMS), 259 Functional Outcomes of Sleep Questionnaire
Dim light melatonin onset (DLMO), 284, (FOSQ), 260
292, 293
Doxepin, 274
Driving drowsy, 75 G
Driving risk assessment Gabapentin, 35
alcohol literature Gamma amino butyric acid (GABA), 18
impairments, 138 Gastric bypass surgery, 397
legal remedies, 140 Gastrointestinal system, 10–11
neurocognitive functions, 139 Growth hormone, 10
excessive sleepiness, 132
factors, 133–135
interactive responsibilities, H
135–136 Heart rate variability, 9
pulmonary physicians High altitude sickness
liability risk, 136–137 acetazolamide, 264
principles, 140–141 acute mountain sickness, 263
self reported sleepiness, 133 benzodiazepines, 264–265
sleepiness impacts, 132 non-benzodiazepine benzodiazepine
societal implications, 138 receptor agonists, 265
Drowsiness, 131DSPD. See Delayed sleep oral steroids, 266
phase disorder (DSPD) High-altitude sleep (HAS), 263
Home mechanical ventilation (HMV), 262
Human leukocyte antigens (HLA), 309
E Hypercapneic ventilatory responses
Endocrine hormones, 10 (HCVR), 258
End-tidal carbon dioxide tension (ET-CO2), Hypercapnia, 5
257, 258, 392 Hyperpnea, 224
Epworth Sleepiness Scale (ESS), 60, 81–83 Hypersomnia. See Daytime sleepiness
Erythropoietin, 210 Hypertension, 126–127
Esophageal sphincter, 10 Hyperventilation, 227
410 Index

Hypnotics medication history, 248–250

BZRAs, 267 psychiatric history, 248
COPD, 268, 269 sleep history, 247
CPAP, 269, 270 cognitive-behavioral therapy, 275
eszopiclone, 270 cognitive behavioral treatment, 249
FDA, 267 comorbidity, 240, 241
FEV1, 268, 269 control of breathing
non-benzodiazepine BZRAs, 268, 270 ETCO2, 257, 258
ramelteon, 270–271 hypercapnea and hypoxia, 258
SDB, 269 NREM and REM, 257, 258
Hypocapnia, 5, 224 ventilation, 257
Hypocapnic apneic threshold, 5 wakefulness, 257
Hypocretin antagonist, 36 definition, 255
Hypopharyngeal surgery DSM-IV, 242
anatomy, 197–198 functional outcomes, 250
hypopharyngeal surgical techniques, ICSD-II
199–200 acute insomnia, 243
Hypothyroidism, 122 frequency and severity, 242–243
Hypoventilation subtype, 242
central sleep apnea, 226 medications
measurement, 209 BZD anxiolytics, 276
rapid eye movement, 208, 209 efficacy of hypnotics, 267–271
Hypoxemia melatonin receptors, 273
clinical consequences, 209–210 non-benzodiazepine BZRAs, 272
diagnosis, 210 OTC sleep medications, 275–276
interstitial lung diseases, 260 ramelteon, 273
pathophysiology, 214–215 risk of abuse, 271–272
treatment, 210–211 total ventilation, 272
triazolam, 273
mental disorder, 241
I pathophysiology
ICSD. See International Classification financial strain, 246
of Sleep Disorders (ICSD) maladaptive behaviors, 246–247
ICSD-II. See International Classilcation predisposition, 245, 246
of Sleep Disorders-II (ICSD-II) sleep reactivity, 246
ICU. See Intensive care unit (ICU) stress, 246
Idiopathic hypersomnia, 85 population-based studies, 255
clinical features, 308 prevalence and risk factors
diagnosis, 313–314 children and adolescents, 244
differential diagnosis, 314–315 medication, 245
epidemiology, 309–310 meta-analysis, 244
pathophysiology, 311 mortality, 245
treatment race vs. age, 244
nonpharmacologic management, 316 pulmonary disorders
pharmacologic management, 316–317 bronchospastic airway disorders, 259
ILD. See Interstitial lung diseases (ILD) high altitude sickness, 263–266
Insomnia, 18 interstitial lung diseases, 259–261
antidepressants kyphoscoliosis, 261–262
doxepin, 274 restrictive thoracic cage disorders,
trazodone, 274–275 261–262
behavioral treatments, 249 Intensive care unit (ICU)
clinical assessment light and temperature, 410
family history, 248 noise environment, 410
medical history, 248 sleep fragmentation, 408
Index 411

International Classification of Sleep dental-based treatment, 173

Disorders (ICSD), 225 dental considerations, 166
International Classilcation of Sleep long-term efficacy, 164
Disorders-II (ICSD-II), 242–243 mechanism, 161, 162
Interstitial lung disease neurocognitive function, 163
diagnosis, 215 OSA treatment, 160
treatment, 216 treatment outcome, 167, 168
Interstitial lung diseases (ILD), 259–261 upper airway neuromuscular function, 161
Interstitial pulmonary fibrosis (IPF), 259–261 Maxillomandibular advancement surgery
Intervention protocols, OSA patients (MMA), 200–201
gastric bypass surgery patients, 397 Medication
general surgery, 396 daytime sleepiness, 77
orthopedic surgery, 396–397 insomnia
IPF. See Interstitial pulmonary fibrosis (IPF) clinical assessment, 248–250
Irregular sleep–wake rhythm hypnotic effects, 267–271
diagnosis, 290–291 prevalence and risk factors, 245
treatment, 291 nocturnal hypoxemia, 211
Isolated recurrent sleep paralysis Melatonin, 31
clinical symptomatology, 336 Metabolic syndrome, 128–129
definition, 336 Mirtazapine, 35
diagnostic workup, 337 Modafinil, 37–41
epidemiology, 336 Monoamine oxidase inhibitors, 35
etiology, 336 Movement disorders
pathophysiology, 336 periodic limb movement disorder,
treatment, 337 365–367
restless legs syndrome, 360–364
sleep-related bruxism, 370–371
J sleep-related leg cramps, 367–369
Jet lag sleep-related rhythmic movement
diagnosis, 294 disorder, 372–374
treatment, 294–295 Multiple sleep latency test (MSLT), 69–70,
79–80, 312, 313

K
Kyphoscoliosis N
diagnosis, 215 Narcolepsy, 83
respiratory mechanics, 214 central nervous system, 79
therapy, 215 chronic neurologic condition, 84
Kyphoscoliosis (KS), 261–262 clinical features, 306–308
diagnosis, 311–313
differential diagnosis, 314–315
L epidemiology, 309
Long-term efficacy, 160, 164, 170 nonpharmacologic management, 316
pathophysiology, 310–311
pediatric patients, 312
M pharmacologic management
Maintenance of Wakefulness Test (MWT), cataplexy, 317
80–81 fragmented nocturnal sleep, 318
Mandibular advancement splints (MAS) sodium oxybate, 316
adverse effects, 172 Narcolepsy with cataplexy, 311, 312
cardiovascular endpoints, 163 Narcolepsy without cataplexy, 311, 312
vs. CPAP, 164–165 Nasal surgery
daytime sleepiness, effects, 163 allergic rhinitis and sleep, 185–186
dental and skeletal changes, 172 anatomy, 184–185
412 Index

Nasal surgery (cont.) nonrapid eye movement, 1, 3

nasal obstruction upper-airway structure and function
sleep-disordered breathing, 188 alveolar ventilation, 7
sleep disturbance, 187–188 chemical and mechanical
surgical treatment, 188–189 perturbations, 6
OSA medical therapy, 189–190 collapsibility, 8
physiology, 184–185 critical closing pressure, 8
National Health Interview Survey, 244 hypoventilation, 7
National Institutes of Health State-of-the- inspiratory-flow limitation, 6, 7
Science Conferene, 240 pharyngeal airway and
National Sleep Foundation, 245, 247 nasopharyngoscopy, 7
NE. See Norepinephrine (NE) pharyngeal compliance, 7–8
Nightmares pharyngeal muscles, 6
clinical symptomatology, 337 REM sleep, 6
corticosteroids, 412 sleep continuity, 7
definition, 337 Starling resistor model, 8
diagnostic workup, 338 tidal volume and hypoventilation, 5
epidemiology, 338
etiology, 338
pathophysiology, 338 O
treatment, 338–339 Obesity, 103–104, 119
NIPPV. See Non-invasive positive pressure Obesity hypoventilation syndrome (OHS)
ventilation (NIPPV) clinical features, 217
Nocturnal hypoxemia diagnosis, 217
diagnosis, 210 pathogenesis, 216–217
FSS scores, 260 therapy, 217–218
treatment, 210–211 weight loss, 218
Nonbenzodiazepine receptor agonists Obstructive apnea systematic intervention
efficacy studies, 22–27 strategy (OASIS), 394, 395
side effects, 20–22 Obstructive sleep apnea (OSA)
Non-invasive positive pressure ventilation adverse consequences
(NIPPV), 212, 231, 261, 262 arrhythmias, 128
Nonrapid eye movement (NREM), 3 cardiovascular consequences,
homeostatic mechanisms, 1 125–126
hypocapnia, 223–224 coronary artery disease, 127
NREM parasomnias diabetes, 128–129
confusional arousal, 325–327 hypertension, 126–127
sleep terror/pavor nocturnus, 330–332 metabolic consequences, 125–126
sleepwalking/somnambulism, metabolic syndrome, 128–129
327–330 stroke, 127
N1 sleep stage, 1, 3 symptoms, 125
N2 sleep stage, 3 apnea–hypopnea index, 94
N3 sleep stage, 3 autotitrating positive airway pressure,
Norepinephrine (NE), 317 68–69
Normal human sleep clinical definition
breath control, 5, 6 AASM, 95
cardiovascular function, 9 excessive daytime sleepiness, 977
chemoresponsiveness, 5 hypopnea, 95–96
endocrine function, 10 nasal pressure/thermal sensors, 96–97
gastrointestinal function, 10–11 respiratory events, 95
sleep architecture, 3–4 clinical history, 59–61
sleep stages clinical symptoms, 122–123
ECG characteristics, 1, 2 and COPD, 212
full wakefulness, 1 definition, 57
Index 413

disease progression, 102–103 prevalence study

full-night polysomnography, 94 Asia, 98–99, 101
future outlook, 70 Australasia, 99, 102
intervention protocols Europe, 98, 100–101
gastric bypass surgery patients, 397 North America, 98, 100
general surgery, 396 South America, 99, 101–102
orthopedic surgery, 396–397 prevention, 179
intraoperative management primary consequences, 118–119
anesthetics/anesthetic technique, risk factors, 58–59
388–389 age, 105, 120
tracheal intubation, 389–390 alcohol and cigarette consumption,
multiple sleep latency test, 69–70 108–109
oral appliances bony structures, 121
adverse effects, 171–172 co-morbid conditions, 122
appliance titration protocols, craniofacial features, 106–107
170–171 edematous states, 121
contraindications, 169 ethnicity, 107–108, 120–121
CPAP vs. MAS, 164–165 familial factors, 109
dental considerations, 166 gender, 105–106
future research, 173–174 genetic factors, 109
health outcome, 163–164 hypothyroidism, 122
indications, 166 menopause and pregnancy, 105–106
interdisciplinary care model, 173 obesity, 103–104, 119
long-term efficacy, 164 positive family history, 121–122
mechanism, 160–161 sex, 120
outcome techniques, 167–169 split night study, 65
polysomnographic outcomes, surgical therapy
162–163 hypopharyngeal surgery, 196–200
treatment adherence, 172–173 maxillomandibular advancement
treatment success, 166–167 surgery, 200–201
types, 159–160 nasal surgery, 184–189
overnight full polysomnography, 116, 118 oropharyngeal surgery, 190–196
overnight polysomnography, 62–65 PAP, 180
PACU, 392–396 patient evaluation, 182–183
physical exam, 62 role of, 181–182
physical signs, 123–124 snoring, 183–184
portable monitoring, 66–68 OHS. See Obesity hypoventilation syndrome
postoperative monitoring (OHS)
capnography, 392 Oropharyngeal surgery
oximetry, 391 palatal anatomy and examination,
postoperative pain control, 390–391 192–193
preoperative evaluation paradigm shift, 190–191
American Society of Anesthesiologists’ surgical techniques
checklist, 384 expansion sphincter pharyngoplasty,
Berlin questionnaire, 384 194–195
morbid obesity, 383 transpalatal advancement, 195–197
positive airway pressure therapy, 386, uvular preservation, 191
387 uvulopalatopharyngoplasty, 190
preoperative OSA optimization, 388 Orthopedic surgery, 396–397
Sleep Apnea Clinical Score, 385–387 OSA. See Obstructive sleep apnea (OSA)
STOP-Bang model, 385 Overlap syndrome, 212
STOP questionnaire, 384 Overnight full polysomnography, 116, 118
surgical patients, 382–383 Overnight polysomnography, 62–65
prevalence and epidemiology, 58 Oximetry, 391
414 Index

P Polysomnography (PSG), 94, 210, 229, 240,

PACU. See Postanesthesia care unit (PACU) 243, 249
Parasomnia overlap syndrome, 335 Portable monitoring (PM)
Parasomnias decision-making diagram, 68
catathrenia, 346–347 one-size-fit-all approach, 67
exploding head syndrome, 346 vs. PSG cost effectiveness, 69
NREM types, 66–67
confusional arousal, 325–327 Positive airway pressure (PAP) therapy, 180
sleep terror/pavor nocturnus, 330–332 Postanesthesia care unit (PACU),
sleepwalking/somnambulism, 327–330 392–396
REM Postoperative monitoring, OSA patients
isolated recurrent sleep paralysis, capnography, 392
336–337 oximetry, 391
nightmares, 337–339 Post polio syndrome, 214
parasomnia overlap syndrome/status Pressure relief positive airway pressure
dissociates, 335 (PRPAP), 154
REM sleep behavior disorder, 332–335 Prolactin, 10
sleep enuresis, 340–344 Protriptyline, 211
sleep-related dissociative disorder, Pulmonary disorders
339–340 bronchospastic airway disorders, 259
sleep-related eating disorder, 344–345 high altitude sickness
sleep-related hallucinations, 347–348 acetazolamide, 264
Pavor nocturnus. See Sleep terror acute mountain sickness, 263
Periodic leg movements (PLMs), 32, 35, 243, benzodiazepines, 264–265
351, 365 non-benzodiazepine benzodiazepine
Periodic limb movement disorder (PLMD) receptor agonists, 265
associated features, 366 oral steroids, 266
demographics, 365 interstitial lung diseases, 259–261
diagnosis, 365 kyphoscoliosis, 261–262
differential diagnosis, 366 restrictive thoracic cage disorders,
management, 366–367 261–262
Pharmacologic therapy, 231–232 Pulmonary hypertension, 149
Pharmacology
agomelatine, 36–37
almorexant, 36 R
antihistamines, 35 Ramelteon
drug development, 45 drug–drug interactions, 27–28
gabapentin, 35 drug efficacy and tolerance, 28–30
sedatives and stimulants, 17 pharmacologic characteristics, 27
sleep-promoting drugs side effects, 28
antidepressants and antipsychotics, Rapid eye movement (REM), 6
30–35 clinical symptomatology, 332–333
barbiturates derivatives, 27 definition, 332
benzodiazepines, 18–20 diagnostic workup, 333
melatonin, 31 epidemiology, 333
melatonin receptor agonists, 27–30 etiology, 333
nonbenzodiazepine receptor agonists, hypoventilation, 208, 209
20–27 parasomnias
stimulants/wake-promoting drugs isolated recurrent sleep paralysis,
amphetamine-like substances, 37 336–337
armodafinil, 41–42 nightmares, 337–339
modafinil, 37–41 parasomnia overlap syndrome/status
sodium oxybate, 42–44 dissociates, 335
Pittsburgh Sleep Quality Index (PSQI), pathophysiology, 333
260, 263 treatment, 333–335
Index 415

Respiratory effort-related arousals (RERAs), sleep fragmentation, 408

63, 94 sepsis model, 406
Restless legs syndrome (RLS) Sleep apnea
associated features, 361 pulmonary physicians, 136
demographics, 360 risk factor, 135
diagnosis, 360–361 societal implications, 138
differential diagnosis, 362 treatment, 133
management Sleep Apnea Clinical Score (SACS), 385–387
dopaminergic therapy, 364 Sleep architecture, 3–4
non-pharmacological and Sleep disordered breathing (SDB), 269
pharmacological treatments, Sleep enuresis
363, 364 clinical symptomatology, 340–341
opioids, 364 definition, 340
primary vs. secondary factors, 362–363 diagnostic workup, 341
Restless leg syndrome, 84–85 epidemiology, 341
Restrictive lung disorders etiology, 341
chest wall disorders pathophysiology, 341
diagnosis, 215 treatment, 342–344
pathophysiology of hypoxemia, Sleep-promoting drugs
214–215 antidepressants and antipsychotics
therapy, 215 bupropion, 35
interstitial lung disease mirtazapine, 35
diagnosis, 215 monoamine oxidase inhibitors, 35
treatment, 216 SSRI and SNRI, 32–34
Restrictive thoracic cage disorders (RTCD), trazodone, 31–32
261–262 tricyclic antidepressants, 32
barbiturates derivatives, 27
benzodiazepines
S hang over effects, 19
SACS. See Sleep Apnea Clinical Score insomnia, 18
(SACS) pharmacokinetics and dosing, 20
SCN. See Suprachiasmatic nucleus (SCN) melatonin, 31
Serotonin and norepinephrine reuptake melatonin receptor agonists, 27–30
inhibitor (SNRI), 32–34 ramelteon, 27–28
Shift work disorder tasimelteon, 31–32
diagnosis, 292 nonbenzodiazepine receptor agonists
treatment, 292–294 efficacy studies, 22–27
Short-term potentiation (STP), 224 side effects, 20–22
Single photon emission computerized Sleep-related bruxism
tomography (SPECT), 328 associated features, 371
Sinus arrhythmia, 9 demographics, 370
Sleep and critical illness diagnosis, 370, 371
causes and cures differential diagnosis, 370
benzodiazepines, 411 management, 371
dexmedetomidine, 412 Sleep-related dissociative disorder,
mechanical ventilation, 410 339–340
noise environment, 410 Sleep-related eating disorder (SRED)
physiological level, 411 clinical symptomatology, 344–345
pressure support, 411 definition, 344
sleep disruption, 409 diagnostic workup, 345
measurement, 407–408 epidemiology, 345
nature and extent etiology, 344
circadian rhythm, 409 pathophysiology, 344
decreased REM sleep, 408 treatment, 345
416 Index

Sleep-related hallucinations, 347–348 Split night study, 65

Sleep-related leg cramps SRED. See Sleep-related eating
associated features, 368 disorder (SRED)
demographics, 367–368 Starling resistor model, 8
diagnosis, 367 Stimulants/wake-promoting drugs
differential diagnosis, 368 amphetamine-like substances, 37
treatment, 368–369 armodafinil, 41–42
Sleep-related rhythmic movement disorder modafinil, 37–41
associated features, 373 sodium oxybate, 42–44
demographics, 372 STOP-Bang model, 385
diagnosis, 372–373 STOP questionnaire, 384
differential diagnosis, 373 STP. See Short-term potentiation (STP)
treatment, 374 Stroke, 127
Sleep terror Suprachiasmatic nucleus (SCN), 283, 284
clinical symptomatology, 330–331
definition, 330
diagnostic workup, 331 T
epidemiology, 331 Tasimelteon, 31–32
etiology, 331 Thyroid-stimulating hormone (TSH), 10
pathophysiology, 331 Tongue retaining devices (TRD), 159, 160
treatment, 331–332 Transpalatal advancement surgery, 195–197
Sleepwalking Traumatic brain injury (TBI), 315
clinical symptomatology, 327–328 Trazodone, 274–275
definition, 327 Tricyclic antidepressants (TCA), 32, 317
diagnostic workup, 329
epidemiology, 329
etiology, 328 U
pathophysiology, 328 Upper airway reflexes, 224
treatment, 329–330 Uvulopalatopharyngoplasty (UPPP), 190
Snoring, 183–184
Sodium oxybate
drug efficacy, 42, 44 W
side effects, 44 Wake after sleep onset (WASO), 267, 268
Somnambulism. See Sleepwalking Wisconsin Sleep Cohort Study, 98, 100