Critical Care Cli

Crit Care Clin 24 (2008) xiii
Erratum
In the January 2008 issue of Critical Care Clinics, Volume 24, Number 1,
in Dr. Charles W. Hogue’s article, ‘‘Mechanisms of Cerebral Injury from
Cardiac Surgery’’ starting on page 83, an error was made in the section titled
‘‘Hyperglycemia.’’ On page 90 the sentence should read, ‘‘A subsequent trial
using a similar protocol in medical ICU patients found lower morbidity
but higher mortality in patients receiving intensive insulin treatment who
required less than 3 days of ICU admission compared. . .’’
0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2008.04.001 criticalcare.theclinics.com
Crit Care Clin 24 (2008) xi–xii
Preface
Nancy A. Collop, MD
Guest Editor
Sleep is a basic physiologic function of the human body. It is required to

maintain health and to assist in recovery from disease. Unfortunately the
hospital environment is not a very conducive environment for restful sleep.
The ICU is one of the harshest environments for maintaining necessary
sleep and circadian rhythms. In this issue of Critical Care Clinics, we explore
many different aspects of sleep and circadian rhythms and how their disrup-
tion may affect the patient hospitalized in the ICU.
The initial article reviews what occurs during normal sleep, examining its
effects on not only the central nervous system but also other physiologic sys-
tems. The second article delves into the dramatic effects caused by sleep dep-
rivation, an obvious result of the ICU environs.
The next two articles analyze medication effects. One article looks at the
effects on sleep of the drugs that are commonly used in the ICU setting, an
analysis not often considered when using these medications. Because sleep
disorders are extremely common, the second article is included to review
the effects of common medications used to treat sleep disorders. The pur-
pose of including this article is to familiarize the intensivist with these med-
ications, which they may not use regularly.
The next article examines another potential disruptor of sleep in the ICU,
artificial ventilation. Both invasive and noninvasive ventilation have been
shown to have adverse effects on sleep and some studies suggest this disrup-
tion may potentially lead to prolonged time for weaning.
The next four articles are dedicated to examining sleep disorders that
are commonly found in patients admitted to ICUs, including
xii PREFACE
obesity-hypoventilation syndrome, the overlap syndrome (patients who

have both COPD and obstructive sleep apnea), and heart failure compli-
cated by sleep-disordered breathing syndromes. These three articles criti-
cally appraise these syndromes and how they might affect a patient’s ICU
stay. The fourth article reviews sleep disorders that may be concomitantly
found in ICU patients on admission, again alerting the intensivist to ways
these disorders may adversely affect the underlying diagnoses for ICU
admission.
In the final article, we investigate the potential contributors to sleep and
circadian rhythm disruption in the ICU and methods that the ICU director
and staff may use to minimize that impact on their patients.
In conclusion, I hope you find that this issue of Critical Care Clinics
prompts you to consider the impact of sleep, sleep deprivation, and sleep
disorders on your ICU patients and contemplate ways to improve the
ICU environment and the care of your patients’ sleep needs.
I would like to thank the authors for their excellent contributions to this
issue and Lisa Richman for her patience. I dedicate this issue to my hus-
band, Tom Collop, for his love, companionship, and unremitting dedication
to our family.
Nancy A. Collop, MD
Division of Pulmonary/Critical Care Medicine
Johns Hopkins University
1830 East Monument Street, Room 555
Baltimore, MD 21205, USA
E-mail address: ncollop1@jhmi.edu
Crit Care Clin 24 (2008) 449–460
Normal Sleep and Circadian Processes

Nancy A. Collop, MDa,b,*, Rachel E. Salas, MDb,c,
Michael Delayo, BS, RPSGTd,
Charlene Gamaldo, MDb,c
a
Division of Pulmonary/Critical Care Medicine, 1830 East Monument Street, Room 555,
Johns Hopkins University, Baltimore, MD 21205, USA
b
Johns Hopkins Hospital Sleep Disorders Center, 601 North Caroline Street, Suite 1261,
Baltimore, MD 21287, USA
c
Department of Neurology, Johns Hopkins University, 601 N. Wolfe Street,
Meyer 6-113, Baltimore, MD 21287, USA
d
Sleep Services of America, 890 Airport Park Road, Glen Burnie, MD 21061, USA
Sleep is a natural process occurring in animals and human beings. It is

a complicated state involving both behavioral and physiologic processes.
Several brain centers are involved in the production and regulation of sleep
using a variety of hormones, neurotransmitters, and peptides. Sleep can be
differentiated from coma by its reversibility. This article reviews the aspects
of normal sleep, physiologic changes that occur in the human body with
sleep, and how sleep changes over the lifespan.
Normal sleep staging

Sleep is an essential physiologic process for most living organisms. Sleep
is divided into nonrapid eye movement (NREM) sleep and rapid eye
movement sleep (REM). Older sleep staging developed by Rechtschaffen
and Kales [1] divided NREM sleep into four stages, numbered 1, 2, 3,
and 4. According to the newly released American Academy of Sleep Med-
icine scoring criteria, NREM sleep is now characterized by three stages
(N1, N2, N3), with N3 encompassing the older classification of stages 3
and 4 [2]. These stages are based on a constellation of physiologic param-
eters and are defined by electrophysiologic waveforms and frequencies
* Corresponding author. Division of Pulmonary/Critical Care Medicine, 1830 East

Monument Street, Room 555, Johns Hopkins University, Baltimore, MD 21205.
E-mail address: ncollop1@jhmi.edu (N.A. Collop).
450 COLLOP et al
using electroencephalographic (EEG) monitoring. Sleep stage 1 (N1) com-

prises about 2% to 5% of sleep and consists of a low voltage, mixed fre-
quency pattern, usually in the theta range (4 Hz–8 Hz) that has
transitioned from the alpha rhythm (8 Hz–13 Hz) seen in wakefulness
(Figs. 1 and 2).
Sleep stage 2 (N2), which usually lasts for approximately 10 to 25 minutes
each time it cycles, comprises about 45% to 55% of total sleep and is char-
acterized by K-complexes and sleep spindles (Fig. 3). Sleep stages 3 and 4
(N3), also known as slow wave sleep (SWS), make up about 15% to 20%
of total sleep. In the old classification stage 3 was characterized by high volt-
age (75 mV), low-frequency delta waves (less than 2 Hz), accounting for
20% to 50% of an epoch, with stage 4 using the same voltage and frequency
criteria as stage 3, but with the high voltage delta activity accounting for
more than 50% of an epoch (Fig. 4). Sleep stage REM (R) makes up about
20% to 25% of total sleep and is depicted by a low-voltage, high frequency
pattern usually in the theta or beta range (Fig. 5). Stage REM is also char-
acterized by muscle tone attenuation and rapid eye movements. REM sleep
(R) can be divided into phasic REM and tonic REM, depending on certain
criteria (Box 1).
Four to six full NREM-REM cycles are observed during one night. The
first cycle is usually 70 to 100 minutes, compared with 90- to 120-minute cy-
cles thereafter. The SWS cycle length is longest in the first third of the night,
whereas the REM sleep cycle length peaks in the last third of the night. Typ-
ical hypnograms for children, young adults, and the elderly are shown in
Fig. 6.
Fig. 1. Stage Wake (0). This 30-second epoch demonstrates quiet wakefulness. The predomi-
nant rhythm is alpha frequency (8 cps–13 cps) noted in the EEG channels (C3A2, C4A1,
O1A2, O2A1). Alpha rhythm occupying greater than 50% of the 30-second epoch denotes
an epoch of wake.
NORMAL SLEEP AND CIRCADIAN PROCESSES 451
Fig. 2. Stage 1 or N1 sleep. This 30-second epoch demonstrates stage 1 sleep. Stage 1 sleep is
designated by greater than 50% of the epoch filled with theta rhythm (3 cps–8 cps) in the EEG
leads, and slow rolling eye movements.
Sleep-wake cycles: a delicate symphony

The sleep-wake state is a delicate interplay of neurobiologic systems
(Table 1). The Borbely two-process model is the most accepted theory,
which describes the orchestrated balance necessary to achieve a normal
sleep-wake cycle. The two-process model consists of the sleep-wake pro-
pensity, resulting from a combination of an intrinsic circadian pacemaker
(process C) and a homeostatic process (process S). An individual’s
characterized by K complexesdnegative deflection (up) followed by positive deflection (down)
(thick arrow)dor sleep spindles (12 cps–14 cps) (thin arrow). K complexes and sleep spindles
must be 0.5 to 5 seconds in duration.
452 COLLOP et al
designated when 20% to 50% of the 30-second epoch is filled with delta activity (0.5 cps–2 cps,
75uv amplitude). Delta waves are seen from second 18 to 26 on this epoch.
homeostatic sleep drive is directly determined by the duration of wakeful-

ness. In the morning, if there was an adequate amount of sleep, process S
is at it lowest point. As the day proceeds and the duration of wakefulness
is prolonged, process S increases linearly until the person goes to sleep and
henceforth reduces the S drive (Fig. 7). The circadian process C operates
independently of the duration of wakefulness; this process cycles in a fixed
and rhythmic pattern to promote alertness.
Fig. 5. Stage REM or R sleep. This 30-second epoch demonstrates stage REM sleep. This rep-
resents phasic REM with frequent rapid eye movements, chin muscle atonia, and sawtooth
waves (in box).
Box 1. Tonic and phasic REM characteristics

Tonic REM
Appearing throughout a REM period
Electromyographic suppression
Low voltage desynchronized EEG
High arousal threshold
Hippocampal theta rhythm
Elevated brain temperature
Poikilothermia
Olfactory bulb activity
Penile tumescence
Phasic REM
Occurs intermittently during REM period
Rapid eye movements
Middle ear muscle activity
Tongue movements
Somatic muscle-limb twitches
Variability of autonomic activity (cardiac and respiratory)
Ponto-geniculo-occipital spikes
During the day, when the homeostatic sleep drive is mounting, wakeful-
ness is maintained because the circadian process works to offset this rising
drive toward sleep. The timing of circadian rhythm and the homeostatic
sleep drive normally align to achieve fixed and consolidated sleep-wake
schedules. However, individuals can experience a dip in their circadian alert-
ing drive in the late afternoon, which explains the common after-lunch dip
(‘‘siesta’’) in alertness [3]. Under sleep-deprived conditions, the interplay be-
tween the homeostatic and circadian process becomes less coordinated and
the sleep-wake state becomes unstable [4]. During wakefulness, sleep-de-
prived individuals can even display evidence of involuntary sleep intrusions
[5,6]. The circadian after-lunch dip in alertness also becomes amplified in the
face of sleep loss [7,8].
Neurophysiologic centers essential to sleep-wake cycles: overivew

The sleep and wake state are both active neurophysiologic states involv-
ing several neurotransmitters that project to numerous areas along the neu-
roaxis (see Table 1). The posterior hypothalamus, tuberomammillary
nucleus, and regions of the brain stem are all collectively involved in main-
taining wakefulness with the release of excitatory neurotransmitters orexin,
histamine, and acetycholine, respectively, to specific cortical and subcortical
sites. During wakefulness, adenosine, a normal metabolic bioproduct, con-
tinues to build in the system and serves as a soporific neurotransmitter to
454 COLLOP et al
Fig. 6. Hypnograms. Typical hypnograms for children, young adults, and elderly individuals
(From Chokroverty S. Sleep Disorder Medicine, 2nd ed. Boston, Butterworth-Heinemann;
1999. p.11; with permission.)
help transition into the sleep state. Adenosine represents the neurophysio-
logic marker of the homeostatic sleep drive. Therefore, like the process S,
which increases with the duration of wakefulness, so too does the amount
of adenosine along the neuroaxis. Upon entering sleep, normally in the
NREM cycle first, GABA (primarily from the ventral lateral pre-optic nu-
cleus of the anterior hypothalamus) is released to facilitate the sleep state
by inhibiting the excitatory centers involved in maintaining wakefulness. Be-
tween 45 to 120 minutes later the cholinergic REM, on cells in the LDT and
PPT centers of the brain stem as well as the basal forebrain, are activated,
allowing the individual to enter REM sleep.
Recruitment of other centers along the neuroaxis occur in REM sleep, and
for that reason REM is considered the metabolically active sleep cycle. In
fact, REM sleep uses some of the same systems involved in promoting wake-
fulness. The projections and neurotransmitters active in both REM and
NREM also produce a concurrent inhibitory function, thus allowing the in-
dividual to cycle between the NREM and REM states four to five times dur-
ing a typical night, until eventually invoking the wake promoting system.
Table 1
Neurotransmitters of sleep
NORMAL SLEEP AND CIRCADIAN PROCESSES

Neurotransmitter Wake/REM NREM Origin Projections
Gamma aminobutyric ()/þ þþþ ARAS, thalamus, VLPO, Posterior hypothalamus, ARAS, thalamus
acid (GABA) basal forebrain, cortex
Adenosine Increase with þþþþ Diffuse cortical by-product Brain stem and basal forebrain cholinergic cells
wakefulness/þþ of wake state
Histamine þþþþ/þ þþ Posterior hypothalamus Thalamus, brain stem
Acetylcholine (ACH) þþþþ/þþ þ Basal forebrain/LDT/PPT Thalamus, posterior hypothalamus, basal forebrain
Norepinephrine (NE) þþþ/() þþ Locus coeruleus Cortex, hippocampus, thalamus, hypothalamus
Serotonin (SE) þþþ/() þ Dorsal raphe nucleus Same as NE
Orexin/hypocretin þþþþþ/? þ Lateral and posterior hypothalamus Locus coeruleus, dorsal raphe nucleus, LDT, PPT
As demonstrated by the (þ) and () symbols, the impact of these neurotransmitters involves the timing of their release during the specific phases as well as
their inhibitory or excitatory role at their projected sites. The role of some neurotransmitters are still unclear in some of the phases, as demonstrated by the (?)
of the impact of orexin/hypocretin during REM sleep.
Abbreviations: ARAS, Ascending reticular activating system of the brain stem; LDT: Lateral dorsal tegmentum of the brain stem; PPT, Pedunculopontine
tegmentum of the brain stem; VLPO, Ventro-lateral preoptic nucleus of the anterior hypothalamus.
455
456 COLLOP et al
Fig. 7. Process C and process S. The two-process model involving a sleep homeostatic process
(S) and a circadian process (C). (From Chokroverty S. Sleep Disorder Medicine, 2nd ed. Boston,
Butterworth-Heinemann; 1999. p.143; with permission.)
Sleep-wake cycles over the lifespan

From birth to age 1 the sleep stages are less clearly defined. Infants typ-
ically go to sleep via ‘‘active sleep,’’ which is most similar to adult REM
sleep. Sleep periodicity is less, typically 50 to 60 minutes, and is throughout
the 24-hour period rather than consolidated into nighttime. As infants be-
come young children, they develop more slow wave sleep, which may com-
prise one third to one half of the sleep period. Slow wave sleep decreases
dramatically during the second decade and that decrease continues through-
out the lifespan [9]. Aging as adults is associated with increased nocturnal
awakenings, prolonged time awake after onset of sleep, decreased sleep ef-
ficiency [10–12], and decreased slow-wave sleep [13]. There is a weakening
of homeostatic processes in the regulation of sleep and waking, such that
maintaining alertness throughout the waking day is challenged by failure
to consolidate sleep at night. REM sleep remains relatively stable through-
out the lifespan, following the early years when it comprises approximately
50% of sleep time.
Older individuals have a more difficult time maintaining alertness in the
late afternoon and evening than younger individuals. These findings suggest
that the body’s circadian arousal signal (process C) fades with age [14].
There is an age-dependent impairment in phase shifting, and flattening of
the diurnal sleep-wake rhythm amplitude, resulting in increased daytime
napping of the elderly.
Physiologic changes during sleep

Cardiovascular
NREM and REM states profoundly affect cardiovascular processes. In
NREM sleep, there is autonomic stability with dominance of parasympa-
thetic tone and vagal nerve input. This results in prominent sinus
arrhythmia, with coupling of respiratory variation. During inspiration,

heart rate increases to accommodate the increased venous return and during
expiration, heart rate slows. This pattern is normal and suggests normal
functioning; reduced heart rate variability is seen in disease states and
with aging. In severe coronary disease, the relative bradycardia and hypo-
tension associated with NREM sleep may result in sleep associated
ischemia.
REM sleep results in significant changes in sympathetic nervous system
tone with marked activation occurring in conjunction with intense rapid
eye movements. These phasic REM periods cause increases in heart rate
and blood pressure by as much as 35% [15]. These phasic periods have
also been associated with significant reduction in coronary artery flows in
situations of severe coronary stenosis [16]. In contrast, abrupt decreases in
heart rate are also noted in REM sleep, primarily during the tonic phase
of REM. This is thought to occur because of increased vagus nerve tone
and suppression of sinus node activity. The transitions from NREM to
REM have also been noted to result in both heart rate increases as well
as pauses and even frank asystole.
Respiratory
The onset of sleep is associated with significant changes in ventilation.
Minute ventilation falls with sleep onset and arterial partial pressure of car-
bon dioxide rises. This is predominately because of a decrease in tidal vol-
ume, with little change in respiratory rate. In REM sleep, minute
ventilation falls even further; respiratory rate is much more irregular again,
with the most variability observed during the phasic part of REM. It is
thought that during NREM sleep, metabolic control of ventilation is pre-
dominant, whereas during REM sleep, behavioral control is more active, al-
though metabolic control continues to play a role [17].
The carbon dioxide concentration is one of, if not the, most potent ven-
tilatory determinants. However with sleep onset, carbon dioxide levels in-
crease progressively through the NREM stages and into REM. The
hypercapnic ventilatory response therefore clearly falls with sleep onset
and the slope is progressively decreasing from wake to NREM to REM
(Fig. 8). This fall in the hypercapnic response may be less in females. Hyp-
oxic ventilatory responses fall in both genders during REM sleep; but there
is less change in females during NREM sleep (Fig. 9). Similarly, there are
different thresholds to arouse from sleep. In hypoxic conditions, arousals
occur at lower oxygen levels in REM sleep compared with NREM. During
hypercapnic conditions, the stimulus to arouse requires the highest carbon
dioxide levels during N3 sleep compared with N1, N2, or REM [18].
Another effect on respiration during sleep involves the upper airway mus-
cle tone. Upper airway muscle activity is reduced with sleep onset, resulting
in an increase in transpulmonary resistance. This increase in upper airway
458 COLLOP et al
Fig. 8. Ventilatory response to O2 with sleep stages. This figure represents the change in minute
ventilation in response to decreasing oxygen saturation levels that occur during the different
stages of sleep. Gray line ¼ REM, Dotted line ¼ Stage 2, Broken line ¼ Stages 3/4, Black
line ¼ Awake.
resistance causes the reduction in minute ventilation [19]. Additionally, neu-

romechanic input, the pattern of inspiratory airflow, the air temperature,
and the phase of the respiratory cycle can further alter upper airway muscle
activity during sleep.
Endocrine
Perhaps no physiologic system of the human body is more sensitive to
sleep and circadian rhythms than the endocrine system. Most hormones
fluctuate their levels according to a circadian rhythm or with sleep/wake cy-
cles. Growth hormone (GH) and prolactin (PRL) secretion are essentially
absent when sleep does not occur. GH tends to have its highest pulsation
associated with the first NREM sleep period. This is much more consistent
Fig. 9. Ventilatory response to carbon dioxide with sleep stages. This figure represents the
change in minute ventilation in response to increasing carbon dioxide levels that occur during
the different stages of sleep. Gray line ¼ REM, Broken line ¼ Stage 2, Dotted line ¼ Stages 3/4,
Black line ¼ Awake.
in men than in women, and GH secretion also tends to decrease with age, in
a similar pattern as the percentage of N3 sleep decreases [20]. PRL levels in-
crease with sleep onset and are also associated with stage N3 (deep sleep),
with a similar age related decline occurring in both.
Most other hormone levels fluctuate with circadian rhythms, including
cortisol, thyrotropic hormones, and those related to glucose metabolism
and appetite. Adrenocorticotropic hormone and cortisol tend to increase
in the early hours of the morning and decline through the day, with the low-
est levels around midnight. Sleep deprivation, either total or partial, results
in overall increase in evening cortisol levels, which have been postulated to
potentially facilitate abnormalities associated with glucocorticoid excess,
such as insulin resistance. Indeed, when glucose tolerance is measured dur-
ing periods of chronic sleep deprivation, the insulin response is dramatically
slower when compared with before and after the sleep deprivation episodes
[21].
Thyroid stimulating hormone synchronizes with circadian rhythm and
body temperature, with peak levels associated with the beginning of sleep
followed by a continuing decline during sleep. Chronic sleep deprivation re-
sults in overall reduction of thyroid stimulating hormone levels.
Gastrointestinal
Gastrointestinal function is altered during sleep. There is a circadian
rhythm in basal gastric acid secretion, with the peak in secretion actually oc-
curring during the first few hours of sleep. The acid levels do not correlate
with sleep stages. The effect of sleep on gastric and intestinal motility are in-
consistent and likely small, if present. Salivary flow is reduced, as is the fre-
quency of swallowing.
Esophageal function has been studied intensely because of the association
with reflux [22]. The upper esophageal sphincter tone changes little during
sleep. The motility of the esophagus is reduced during sleep, with the fre-
quency of both primary and secondary contractions progressively diminish-
ing from stages N1 to N3, but secondary contractions increase during REM.
The lower esophageal sphincter has transient reductions in tone, which are
conducive to reflux episodes. Additionally, acid clearance time is typically
prolonged during sleep.
Summary
Sleep is associated with distinct changes in not only the central nervous
system but all physiologic systems. These distinct changes vary considerably
between the different stages of sleep and become altered more with aging. In
subsequent articles in this issue, it will be demonstrated how sleep depriva-
tion, medications and different sleep disorders disrupt the delicate balance of
these physiologic systems.
460 COLLOP et al
References
[1] Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring
systems for sleep stages of human subjects. Los Angeles (CA): UCLA Brain Information Ser-
vice/Research Institute; 1968.
[2] Iber C, Ancoli-Israel S, Chesson A, et al. The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications. 1st edition. Westches-
ter (IL): American Academy of Sleep Medicine; 2007.
[3] Carskadon MA, Dement WC. Multiple sleep latency tests during the constant routine. Sleep
1992;15:396–9.
[4] Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol
2005;25:117–29.
[5] Akerstedt T. Sleep/wake disturbances in working life. Electroencephalogr Clin Neurophy-
siol Suppl 1987;39:360–3.
[6] Torsvall L, Akerstedt T. Sleepiness on the job: continuously measured EEG changes in train
drivers. Electroencephalogr Clin Neurophysiol 1987;66:502–11.
[7] Bonnet MH, Arand DL. 24-hour metabolic rate in insomniacs and matched normal sleepers.
Sleep 1995;18:581–8.
[8] Bonnet MH, Arand DL. The consequences of a week of insomnia. Sleep 1996;19:453–61.
[9] Carskadon M, Dement W. Normal human sleep: an overview. In: Kryger M, Roth T, De-
ment W, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier
Saunders; 2005. p. 13–25.
[10] Bliwise DL, King AC, Harris RB, et al. Prevalence of self-reported poor sleep in a healthy
population aged 50–65. Soc Sci Med 1992;34:49–55.
[11] Gerard P, Collins KJ, Dore C, et al. Subjective characteristics of sleep in the elderly. Age
Ageing 1978;(Suppl):55–63.
[12] Hayter J. Sleep behaviors of older persons. Nurs Res 1983;32:242–6.
[13] Bliwise DL, King AC, Harris RB. Habitual sleep durations and health in a 50–65 year old
population. J Clin Epidemiol 1994;47:35–41.
[14] Munch M, Knoblauch V, Blatter K, et al. Age-related attenuation of the evening circadian
arousal signal in humans. Neurobiol Aging 2005;26:1307–19.
[15] Dickerson LW, Huang AH, Verrier RL. Relationship between coronary hemodynamic
changes and the phasic events of rapid eye movement in sleep. Sleep 1993;16:550–7.
[16] Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic func-
tion. Am J Physiol 1989;256:H1378–83.
[17] Meza S, Giannouli E, Younes M. Control of breathing during sleep assessed by proportional
assist ventilation. J Appl Physiol 1998;84:3–12.
[18] Krimsky W, Leiter J. Physiology of breathing and respiratory control during sleep. Semin
Respir Crit Care Med 2005;26(1):5–12.
[19] Henke K, Dempsey J, Kowitz J, et al. Effects of sleep-induced increases in upper airway re-
sistance on ventilation. J Appl Physiol 1990;69:617–24.
[20] Copinschi G, Van Cauter E. Effects of aging on modulation of hormonal secretions by sleep
and circadian rhythmicity. Horm Res 1995;43:20–4.
[21] Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine func-
tion. Lancet 1999;354:1435–9.
[22] Orr WC, Johnson LF, Robinson MG. Effect of sleep on swallowing, esophageal peristalsis,
and acid clearance. Gastroenterology 1984;85:814–9.
Crit Care Clin 24 (2008) 461–476
Adverse Effects of Sleep Deprivation

in the ICU
Rachel E. Salas, MDa,*, Charlene E. Gamaldo, MDb,c
a
Department of Neurology, Johns Hopkins School of Medicine, 5501 Hopkins Bayview Circle,
Allergy and Asthma Center–1B.75A, Baltimore, MD 21224, USA
b
Department of Neurology, Johns Hopkins School of Medicine, 5501 Hopkins Bayview Circle,
Allergy and Asthma Center–1B.76A, Baltimore, MD 21224, USA
c
Department of Medicine, Division of Pulmonary/Critical Care, Johns Hopkins
School of Medicine, 5501 Hopkins Bayview Circle, Allergy
and Asthma Center–1B.76A, Baltimore, MD 21224, USA
The hospital is not conducive to sleep. Patients commonly recount ma-

jor issues with sleep initiation and poor sleep quality during their hospital
stay [1]. Moreover, patients in the ICU are particularly susceptible to sleep
disruption secondary to environmental and medical issues. Despite the fre-
quency of sleep disruption in the ICU, the quality of critically ill patients’
sleep is often overlooked. When questioned following discharge from the
ICU, patients frequently report the occurrence of sleep disruption during
their stay, suggesting that sleep disruption in the ICU is widespread. Dis-
turbed sleep patterns result in the undesirable consequences of daytime
sleepiness, lethargy, irritability, confusion, and poor short-term memory
[2]. The potential negative neurologic sequelae from sleep loss may often
lead to additional tests to evaluate for change in mentation (eg, frequent
neurologic checks, head CTs, or MRIs), potentially resulting not only in
an increased financial burden to an already strained health care system
but also in extended hospital stays. Patients requiring additional work-up
because of their sleep-related change in alertness are less able to receive
the care and services, such as physical and occupational therapy, that ben-
efit timely discharges. In fact, increasing evidence supports the concept that
sleep disturbance in the ICU can affect patient mortality during hospitali-
zation and after discharge from the unit. The level of impact of the ICU
experience on a patient seems to be multifactorial; hence, this article
* Corresponding author.
E-mail address: rsalas3@jhmi.edu (R.E. Salas).
462 SALAS & GAMALDO
discusses the following issues essential to understanding the factors associ-

ated with sleep loss in the ICU: (1) core elements to consider from the
baseline sleep history, (2) impact of the ICU environment on the ICU pa-
tient’s sleep pattern, and (3) overall systematic impact of sleep deprivation
on the ICU patient.
Baseline sleep history of the ICU patient

Chronic insufficient sleep: an epidemic at all ages
Insufficient sleep is the most common cause of daytime fatigue and
sleepiness [3] in the general population, and many patients are likely to
suffer from the consequences of insufficient sleep even before their ICU ad-
mission. Inadequate sleep and unhealthy sleep practices are a universal
problem affecting individuals at all ages. In the 2002 National Sleep Foun-
dation annual survey, nearly 40% of adults 30 to 64 years old and 44% of
young adults 18 to 29 years old reported that daytime sleepiness is so se-
vere that it interferes with work and social functioning at least a few
days each month [4]. Older adults average 7.0 hours of sleep on weeknights
and 7.1 hours on weekends [4], whereas younger adults average 6.7 hours
of sleep on weeknights, which increases to 7.6 hours on weekends [4].
Optimal daytime performance with minimal sleepiness seems to require
at least 7.5 to 8.5 hours of sleep at night with few interruptions [4]. An in-
sufficient amount of sleep can result in poor daytime functioning, which
may interfere with patient mortality while in the ICU. It is therefore impor-
tant that ICU physicians are aware of the severe chronic sleep loss often
endured by their patients to minimize aspects of the ICU that could com-
pound the effects of their chronic sleep loss with superimposed hospital-
induced acute sleep loss.
Medical illness
Several studies have shown that underlying medical illness may contrib-
ute to the sleep disruption experienced by patients while in the hospital.
There have been limited studies showing the correlation between the degree
of medical illness and sleep in the ICU; however, the severity of illness may
be an important cause of sleep disturbance. A significant increase in sleep
disruption has been found in patients who have higher disease severity
scores [5]. One study reported that ICU patients who had higher Acute
Physiology and Chronic Health Evaluation (APACHE) scores had a higher
awakening index, shorter sleep time, and decreased slow-wave sleep than
did healthy volunteers in the same environment [6]. Insomnia attributable
to medical conditions is another potential sleep disorder that may be en-
countered in the ICU that is caused by a pre-existing medical condition.
The insomnia may involve a problem with sleep initiation or maintenance,
which impacts overall sleep quality and daytime functioning.
ADVERSE EFFECTS OF SLEEP DEPRIVATION IN THE ICU 463
Sleep and pain

Pain was identified as one of the leading stressors in the hospital by the
patients, relatives, and health care professionals in one survey [7]. Chronic
pain syndromes are known to be associated with alterations in sleep conti-
nuity and sleep architecture. Although studies show that approximately
50% of patients who have various chronic pain syndromes complain of
significant sleep disturbance [8–11], less is known about acute pain in the
ICU. Nonetheless, it has been established that sleep disruption negatively
affects the opioid system and pain perception.
Primary sleep disorders

Many hospitalized patients reported having excessive daytime somno-
lence, insomnia, snoring, and restless legs syndrome before hospitalization
[12]. Primary sleep disorders may result in chronically decreased continuity
of sleep, increased sleep deprivation, and associated impairments in daytime
functioning, including fatigue, cognitive deficits, and excessive daytime
sleepiness. Acutely ill patients who have sleep-disordered breathing, such
as sleep apnea, may develop respiratory failure or have difficulty being
weaned from mechanical ventilation [13,14]. Cardiovascular problems,
such as dysrhythmias, myocardial ischemia, and heart failure, also are asso-
ciated with sleep-disordered breathing [15]. Sleep-disordered breathing is
also common, especially in cardiac patients [16]. Sleep-disordered breathing
may be serendipitously discovered in the ICU because of continuous pulse
oximetry, which has been used in the past as a screener for sleep apnea,
especially in countries with limited resources [17]. Patients who have
sleep-disordered breathing have increased health care costs secondary to
cardiovascular risk and other comorbid conditions, such as obesity, diabe-
tes, and hypertension [18]. For patients who have known sleep apnea, an
attempt to treat with CPAP or bilevel pressure may be of benefit.
The International Classification of Sleep Disordersd2nd edition defines
a circadian rhythm sleep disorder (CRD), ‘‘as a persistent sleep pattern
that is disruptive due to changes in the circadian timekeeping system or mis-
alignment between the endogenous circadian rhythm and societal factors.
The recurrent misalignment results in significant difficulties with sleep initi-
ation or duration that leads to problems with insomnia, excessive daytime
sleepiness, and a decreased level of social and occupational functioning’’
[19]. Individuals across all ages are prone to developing a CRD. Adolescents
are more prone to the CRD delayed phase type that takes on the classic
‘‘night-owl’’ characteristics of late night sleep initiation and late morning/
early afternoon awakenings. The elderly are particularly susceptible to the
CRD advanced phase type, which involves early morning awakenings and
more daytime napping [20,21]. Moreover, elderly who have even a mild
degree of dementia can be susceptible to sundowning, which is another man-
ifestation of circadian rhythm misalignment. Elderly individuals who have
464 SALAS & GAMALDO
visual impairment are more likely to have impaired nighttime sleep than vi-
sually unimpaired elderly subjects [22]. The awareness of patients’ inherent
circadian sleep patterns is crucial to understanding the impact of the ICU
setting on patients’ sleep–wake behaviors.
Rapid eye movement (REM) sleep behavior disorder and other parasom-
nias may also occur during hospitalization in the ICU, which may confound
medical management. Along these same lines, patients who have restless legs
syndrome may report limb dysesthesias associated with an overwhelming
urge to get up out of bed as part of their clinical phenomenology. If these
associated symptoms manifest during hospitalization, these patients may
be perceived as being agitated or confused leading to the use of restraints
and sedation, likely to further exacerbate their symptoms. For this reason,
it is imperative that the ICU treatment team is aware of any pre-existing
sleep disorders that may be exacerbated further in the ICU.
Impact of the ICU environment on sleep: iatrogenic environmental

sleep disorder
Several diverse factors often contribute to poor sleep quality, including
environmental factors, such as noise and ambient light, nursing interven-
tions, medications, patient–ventilator interactions, anxiety, and preexisting
chronic conditions, along with the acute illness itself. The International
Classification of Sleep Disordersd2nd edition defines environmental sleep
disorder, ‘‘as a sleep disturbance due to a disturbing environmental factor
that causes a complaint of either insomnia or daytime fatigue or somno-
lence’’ [19]. The environmental factors disrupting sleep were identified and
include medical interventions, diagnostic procedures, patient–staff interac-
tions, light, and noise, with noise being the most common disruptive envi-
ronmental factor reported in the ICU [23].
Noise
Noise has been found to cause damaging physiologic effects, including
delayed healing [24], impaired immune function [25], and increased blood
pressure [26], heart rate [27], and overall stress [28]. Noise may also increase
medical mistakes [29,30] and impair the concentration and mental efficiency
of the staff [31], which could ultimately increase length of hospital stay and
morbidity of patients. Alarms, phones, televisions, beepers, ventilation ma-
chines, housekeeping, and conversations have all been reported to be major
contributors to ICU noise. Several studies have shown that noise in the ICU
can peak above the recommended values of the Environmental Protection
Agency for day (45 dB) and night (35 dB). Despite the excess noise in the
ICU setting, studies [32,33] have shown that noise only contributes to a small
percentage of arousals and awakenings during sleep, suggesting that there
are indeed multiple factors contributing to disrupted sleep in the ICU.
Synchronous audio, video, and polysomnographic recording in seven venti-

lated patients showed that 20% of the recorded arousals and awakenings
were related to noise and 10% to patient care activities, whereas the causes
of the remaining 70% were not identified, indicating that unknown factors
are also involved [6].
In recent years, some ICUs have implemented various sleep protocols to
address issues such as noise by implementing a quiet time, providing ear
plugs, eliminating intercom use, reducing phone and alarm volumes, closing
doors, and in some cases altering the routine of housekeeping [34]. Some
centers have even incorporated wireless individualized paging to address
the beepers and intercoms. Other interventions, such as soundproofing
hospital rooms, have been considered to decrease noise. Overall, most of
the hospitals that have implemented a sleep protocol report improvement
in their patients’ and families’ level of hospital satisfaction.
Light
Light is also a major cause of sleep disruption in the ICU setting [23]. Light
is the primary environmental cue (zeitgeber) responsible for setting the circa-
dian clock and can shift the phase response curve depending on the timing and
intensity of light exposure. Light levels in the 100 to 500 lux range have been
shown to affect nocturnal melatonin secretion and levels in the 300 to 500 lux
range may have an effect on the human circadian pacemaker [35]. One study
showed that patients in the ICU maintained day–night rhythms over a 7-day
period, with mean maximum light levels ranging from 1602 to 5089 lux during
the day (6 AM–midnight) and 128 to 1445 lux during nighttime hours
(midnight–6 AM) [23]. One might assume that this decrease in light produced
better sleep; however, one study revealed that lowering the light levels induced
a greater variation of light, which may impair sleep quality [36]. Moreover,
another study indicates that dyssynchronization of the melatonin secretion,
which is affected by light, is common in critically ill and mechanically
ventilated patients [37]. It is yet to be determined whether an impairment of
the melatonin rhythm may play a role in the development of sleep distur-
bances and delirium in intensive care patients; therefore, melatonin replace-
ment as a potential treatment option is currently not suggested [38].
Staff–patient interactions
Despite the increased sophistication of monitoring systems in hospitals to-
day, there are still frequent staff–patient interactions leading to sleep disrup-
tion. Studies have found that the mean number of staff–patient interactions
ranged from 42 to 51 per night in the ICU [39,40]. One study found that there
were 8 staff–patient interactions per hour of patient sleep, with most of these
interactions attributable to nursing activities, such as wound dressing, adjust-
ment of intravenous drips, and administration of medications [6]. Nurses
were also found routinely to provide daily baths for patients between 02:00
466 SALAS & GAMALDO
and 05:00 on 55 of the 147 study nights in the ICU [39]. As expected, sleep
disruptions caused by patient interventions or diagnostic tests were found
to vary significantly in different ICUs [33].
Respiration and ventilated ICU patients

Aside from the environmental factors and medical illness severity affect-
ing the sleep patterns of the ICU patient, mechanical ventilation is yet
another factor that confounds overall sleep. The discomfort of the endotra-
cheal tube, inability to communicate adequately, and the stress and anxiety
of being intubated are also experienced by the ventilated ICU patient. But
what about the mechanical ventilation itself and the effect it has on sleep?
There seems to be a circadian pattern to respiration and respiratory control,
even in the absence of sleep. Functional residual capacity, forced expiratory
volumes, and airway resistance change periodically with the time of day.
Resting pulmonary ventilation, tidal volume, and breathing rate also follow
circadian patterns, responding differently to hypercapnia or hypoxia at
various times of the day [41]. Studies in ICU patients have revealed severe
sleep fragmentation in ventilated patients [42]. ICU patients are frequently
unable to entrain their respiratory activity to a mechanical ventilator and
may require heavy sedation and occasionally even paralysis to achieve
satisfactory patient–ventilator synchrony.
Medications
Several medication used in the ICU can cause sleep disruption. For exam-
ple, benzodiazepines may increase sleep time efficiency, decrease sleep
latency, and decrease awakenings, which overall seems to improve sleep
quality and quantity. Nevertheless, benzodiazepines may also decrease
slow wave sleep and REM sleep, increase cortical activity and sleep spindles,
but also decrease EEG amplitude at high doses [43–45]. Narcotics have been
shown to suppress slow-wave sleep and REM sleep and increase arousals
and sleep stage 1 [46]. Inotropic medications, such as dopamine, may cause
cortical activation and therefore increase arousals during sleep also. Further
studies are needed to see the effects of these commonly used medications on
sleep patterns in the ICU setting. Insomnia can be a side effect of several
medications commonly used in the ICU that include antidepressants, anti-
hypertensive agents, hypolipidemic agents, corticosteroids, antipsychotics,
anorectics, antiepileptics, and dopaminergic agents.
Systematic look at the impact of sleep loss on the ICU patient

Impact on sleep quality and quantity
In one study, 29% of patients received a prescription for a hypnotic drug
while in hospital, with no evidence of preadmission hypnotic use [47]. These
data suggest that poor sleep develops during hospitalization and is ubiqui-
tous among patients. In a study by Halfens and colleagues [48], inpatients
who took sleep medication for at least 5 days were more likely to remain
on those sleep medications after discharge home than were patients who
did not receive hypnotics. This finding suggests that inpatient sleep distur-
bance may have some long-term sequelae, although the impact of underly-
ing medical illness cannot be ruled out. Current studies do not allow us to
discriminate between these two potential causes of persistent sleep disorders.
Repetitive whole-night EEG studies, however, demonstrated that normal
sleep patterns did not return to patients who had acute myocardial infarc-
tion until 9 days after discharge from the ICU [49].
Polysomnography (PSG) studies have demonstrated decreased total sleep
time, fragmentation, and altered sleep architecture in ICUs [49–52]. Despite
having a relatively normal amount of sleep in the ICU, approximately 50% of
the total sleep occurs during the day, which suggests that most patients do not
obtain sleep during the optimal nocturnal time frame. A distinct increase in
stage 1 of non-REM sleep and a concomitant decrease in slow-wave sleep
and REM sleep are also apparent in ICU patients [50,52–55]. Recent research
has concluded that sleep cannot be identified by PSG in all critically ill
patients, because of illness- and drug-induced EEG changes. In these patients,
particular EEG features are characteristic of coma and sometimes also a state
of ‘‘pathologic wakefulness,’’ in which behavioral correlates of wakefulness,
such as sustained chin EMG activity, coincide with EEG features of slow-
wave sleep. This finding suggests that the sleep patterns of ICU patients
may be even more affected than believed originally.
Disrupted sleep can also result in added anxiety and pain to patients.
Roehrs and colleagues [56] found that the loss of 4 hours of sleep and
REM-specific sleep loss is associated with hyperalgesia symptoms the
following day. ICU patients are also at risk for developing adjustment
insomnia, which is insomnia in association with an identifiable stressor
that lasts for less than 3 months.
Impact on the cardiovascular system

In a study of cardiovascular autonomic modulation during 36 hours of
total sleep deprivation, the 18 normal subjects studied demonstrated in-
creased sympathetic and decreased parasympathetic cardiovascular modula-
tion and decreased baroreflex sensitivity [57]. In addition, frequent arousals
during sleep are associated with elevated catecholamine release and
increased blood pressure [58].
Insufficient sleep increases the risk for acute myocardial infarction in re-
lation to an elevated activity in the sympathetic nervous system [59,60].
More recently, a case report showing a spontaneous coronary dissection as-
sociated with sleep deprivation presenting with acute myocardial infarction
was described, further supporting the role sleep plays in morbidity [61].
468 SALAS & GAMALDO
Impact on mood
Changes in mood constitute one of the most prominent and consistent
behavioral manifestations of sleep loss [62–65]. During prolonged sleep dep-
rivation, there is an increase in self-reported feelings of depressed mood, an-
ger, frustration, tension, and anxiety [64,66]. Without adequate sleep,
negative reactions to adverse experiences seem to be significantly magnified,
whereas positive reactions to pleasant events are often subdued [67]. Sleep
deprivation is associated with significant reductions in glucose metabolism
within the prefrontal cortex [68], a region of the brain important for person-
ality, emotion regulation, and behavioral inhibition. Sleep deprivation poses
a dual threat to competent decision making by modulating activation in
nucleus accumbens and insula, brain regions associated with risky decision
making and emotional processing [69]. Increased functional MRI brain
responses can be observed after sleep deprivation [70,71], especially when
complex items are studied [72,73]. These studies demonstrate that cortical
function compensates for sleep deprivation initially by recruiting new
regions of the cortex normally dormant when the brain is imaged under
normal sleep-restored conditions [72]. Compensations are maintained up
to the point that the brain becomes so exhausted from sleep deprivation
that the performed task results in a globally diminished response [74].
Impact on mentation
Delirium in the ICU, otherwise known as ICU syndrome, is a well-recog-
nized phenomenon. Currently there has been no documented relationship
between sleep deprivation and delirium. A potential relationship between
these two may lead to heightened attention toward sleep deprivation in
the ICU because sleep deprivation and delirium commonly co-occur. In
this section, evidence suggesting a relationship between sleep deprivation
and ICU syndrome are discussed.
Relationship of sleep deprivation and nightmares to delirium

Intense dreaming and nightmares are often reported by patients in the ICU.
Schelling and colleagues [75] reported that 64% of patients who had acute
respiratory distress syndrome recalled traumatic nightmares during their
stay in the ICU. Between 40% and 57% of the delirious ICU patients report
vivid dreams as one of the main contributors to their spectrum of fluctuating
levels of consciousness, paranoid delusions, and hallucinations [76–78].
Relationship of circadian rhythm disturbance to delirium

Circadian rhythm abnormalities may also contribute to ICU delirium.
Delirious patients in general may display a reversal of the circadian cycle,
with daytime somnolence and nocturnal restlessness and agitation [79].
One type of CRD likely common in the ICU is irregular sleep–wake type,
which is characterized by lack of a clearly defined circadian rhythm of sleep
and wake. The sleep–wake pattern is temporally disorganized so that sleep

and wake periods vary throughout the 24-hour period, which results in spo-
radic bouts of insomnia alternating with somnolence. Predisposing factors
to this sleep disorder include poor sleep hygiene and lack of exposure to
external synchronizing agents such as light, activity, and social schedules.
The rest–activity of an irregular sleep–wake type is depicted in Fig. 1,
illustrating the fragmented episodes of wake and sleep that occur across
each 24-hour period [3].
One other CRD likely to be encountered in the ICU is the free-running
type. The typical internal circadian clock has a cycle length that is slightly
longer than 24 hours. The internal circadian rhythm can only remain aligned
to the 24-hour light–dark cycle through exposure to zeitgebers, such as
sunlight and physical activity. The internal clock relies heavily on a strong
light input during early waking hours and minimal light input during even-
ing hours to remain entrained with a 24-hour cycle. Without this powerful
zeitgeber, the internal clock defaults to its natural 24þ-hour cycle length.
In the ICU setting, zeitgebers, such as light exposure and physical activity,
conducive to entraining the circadian clock are minimal. As a result, a pa-
tient’s natural sleep and wake time shifts to a later time with each successive
day as demonstrated in the actigraphy illustration of a free-running clock
(see Fig. 1) [3].
Some patients who have Alzheimer disease also show a cyclic worsening
of agitation and confusion during the late afternoon to early evening, with
improvement or disappearance of these symptoms during the day. There is
growing evidence that such sundowning behaviors are caused by circadian
disturbances, particularly a phase delay of body temperature [80]. Patients
who have dementia can vary widely in the timing and robustness of their ag-
itation rhythms; for example, Martin and colleagues [81] found that the
peak for agitated behavior in a sample of nursing home residents occurred
in the early afternoon rather than during the evening. A trend for agitation
has been found to worsen in the winter months and in patients awakening
from sleep in darkness [82].
Impact on metabolic/endocrine function

Although little is known regarding the effect of acute sleep deprivation on
metabolic function, studies in rats reveal that chronic sleep deprivation re-
sults in a state of negative energy balance with increased energy expenditure
[83–86], whereas other studies find no change in the hypothalamic-pituitary
axis during sleep deprivation [87,88].
In humans, sleep loss is multifactorial, presenting with other syndromes
that lead to morbidity. Studies also show that sleep-deprived humans,
similar to rats, have elevated metabolic rate [89], increased sympathetic
tone and cortisol [90], and increased food intake concomitant with elevated
serum ghrelin but decreased leptin [90]. Sleep deprivation has been shown to
470 SALAS & GAMALDO
Fig. 1. Activity records of mice. Each record is double-plotted according to convention, so that
each day’s data are presented both to the right of and beneath the day preceding. Times of
wheel-running activity are indicated by dark blue. On days 1 to 6, mice were maintained under
a 12-hour light/12-hour dark cycle. Mice were then transferred to continuous darkness by
allowing lights to go out at the usual time and then to remain off through the remaining
days of data collection. (Top) Activity record of a mouse with an inherent circadian cycle
with a free-running period length of approximately 23.7 hours illustrating an advanced-phase
circadian rhythm disorder. (Middle) Activity record of a mouse with a free-running period
and inherent circadian cycle that lengthened over time to approximately 24.8 hours representing
a delayed-phase circadian rhythm disorder. (Bottom) Activity record of a mouse with a free-
running inherent circadian rhythm process demonstrating an unentrained circadian rhythm
process. (From Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep
medicine. 4th edition. Philadelphia: Elsevier/Saunders; 2005. p. 365; with permission.)
Table 1
Multisystemic effects of acute sleep deprivation on body systems
Disruption of circadian rhythms þ
Basal vasomotor tone þ
Natural killer cells
Antibody titers following influenza virus immunization
Lymphokine-activated killer activity
Interleukin-2 production
Alteration of endocrine and metabolic functions þ
Cortisol release pattern alteration þ
Glucose tolerance þ
Insulin resistance þ
Sympathetic cardiovascular modulation þ
Parasympathetic cardiovascular modulation
Baroreflex sensitivity
Catecholamine release þ
Blood pressure þ
Anxiety þ
Hyperalgesic following day þ
have negative effects on glucose metabolism and to enhance variables asso-

ciated with type 2 diabetes [90].
Impact on immune function

Sleep deprivation has been found to alter immune responses [91] and can
increase circulating levels of inflammatory markers, such as interleukin
(IL)–6, tumor necrosis factor, and C-reactive protein [92–94], with signifi-
cant elevations after only one night of sleep loss [94]. Sleep deprivation
can also result in decreased natural killer cells [95], lower antibody titers
after influenza virus immunization [96], reduced lymphokine-activated killer
activity, and reduced IL-2 production [97].
Nonspecific modulation of the immune response and decreases in aspects
of cellular immune function have been shown in patients undergoing total or
partial sleep deprivation [98]. There is a sleep-dependent increase in IL-7 con-
centration that is associated with increased REM sleep supporting the posi-
tive influence of sleep on T cell function [99]. Healthy adults may show an
increase in IL-6 after only 12 nights of partial sleep deprivation (4 hours
per night) [100]. IL-6 is one of the proinflammatory cytokines associated
with reduced pain tolerance, perhaps identifying one mechanism for com-
plaints of hyperalgesia reported after sleep deprivation. Despite these results,
the effects of sleep loss on the immune system clinically remain speculative.
Summary
Sleep deprivation has been linked to numerous health ramifications
(Table 1). Optimizing sleep quantity and quality in the ICU is vital to
472 SALAS & GAMALDO
a patient’s overall health. Poor sleep can be deleterious to patient outcome

and may lead to further testing resulting in higher medical costs and ex-
tended hospital stays. The medical community needs to be aware of and
avoid potential factors that can promote poor sleep. Strategies for achieving
optimal sleep must involve consideration of the four main topics discussed
in this article. Emphasis on good sleep quality in the ICU remains an impor-
tant concern that has previously been overlooked.
The following elements should be considered to help minimize sleep
disruption in the ICU:
Awareness of patients’ baseline sleep history and patterns is essential for
optimizing their sleep quality in the ICU.
The ICU team should be constantly aware that the commonly prescribed
medications for the ICU may affect sleep.
Noise is the most common environmental sleep disrupter in the ICU.
Light, diagnostic tests, and patient–staff interactions also interfere with
patient sleep quality in the ICU.
Implementing behavioral protocols in the ICU may reduce a patient’s
sleep disturbance, morbidity, and mortality while increasing their over-
all satisfaction.
References
[1] Southwell M, Wistow G. In-patient sleep disturbance: the views of staff and patients. Nurs
Times 1995;91:29–31.
[2] Hodgson LA. Why do we need sleep? Relating theory to nursing practice. J Adv Nurs 1991;
16:1503–10.
[3] Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine. Philadelphia:
Elsevier/Saunders; 2005.
[4] Sleep in America polls–National Sleep Foundation [online]. Available at: http://
www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2417353/k.6764/Sleep_in_America_Polls.
htm. Accessed September 21, 2007.
[5] Parthasarathy S. Sleep during mechanical ventilation. Curr Opin Pulm Med 2004;10:
489–94.
[6] Gabor JY, Cooper AB, Crombach SA, et al. Contribution of the intensive care unit
environment to sleep disruption in mechanically ventilated patients and healthy subjects.
Am J Respir Crit Care Med 2003;167:708–15.
[7] Novaes MA, Aronovich A, Ferraz MB, et al. Stressors in ICU: patients’ evaluation. Inten-
sive Care Med 1997;23:1282–5.
[8] Smith MT, Perlis ML, Smith MS, et al. Sleep quality and presleep arousal in chronic pain.
J Behav Med 2000;23:1–13.
[9] Pilowsky I, Crettenden I, Townley M. Sleep disturbance in pain clinic patients. Pain 1985;
23:27–33.
[10] Morin CM, Gibson D, Wade J. Self-reported sleep and mood disturbance in chronic pain
patients. Clin J Pain 1998;14:311–4.
[11] Ohayon MM. Relationship between chronic painful physical condition and insomnia.
J Psychiatr Res 2005;39:151–9.
[12] Meissner HH, Riemer A, Santiago SM, et al. Failure of physician documentation of sleep
complaints in hospitalized patients. West J Med 1998;169:146–9.
[13] Noureddine SN. Sleep apnea: a challenge in critical care. Heart Lung 1996;25:37–42, quiz
43–4.
[14] Olson EJ, Simon PM. Sleep-wake cycles and the management of respiratory failure. Curr
Opin Pulm Med 1996;2:500–6.
[15] Bradley TD. Sleep disturbances in respiratory and cardiovascular disease. J Psychosom Res
1993;37(Suppl 1):13–7.
[16] Saito T, Yoshikawa T, Sakamoto Y, et al. Sleep apnea in patients with acute myocardial
infarction. Crit Care Med 1991;19:938–41.
[17] Chiner E, Signes-Costa J, Arriero JM, et al. Nocturnal oximetry for the diagnosis of the
sleep apnoea hypopnoea syndrome: a method to reduce the number of polysomnographies?
Thorax 1999;54:968–71.
[18] Bahammam A, Delaive K, Ronald J, et al. Health care utilization in males with obstructive
sleep apnea syndrome two years after diagnosis and treatment. Sleep 1999;22:740–7.
[19] American Academy of Sleep Medicine. International classification of sleep disorders: diag-
nostic and coding manual. 2nd edition. Westchester, IL: Academy of Sleep Medicine; 2005.
[20] Hayter J. Sleep behaviors of older persons. Nurs Res 1983;32:242–6.
[21] Webb WB, Campbell SS. Awakenings and the return to sleep in an older population. Sleep
1980;3:41–6.
[22] Asplund R. Sleep, health and visual impairment in the elderly. Arch Gerontol Geriatr 2000;
30:7–15.
[23] Meyer TJ, Eveloff SE, Bauer MS, et al. Adverse environmental conditions in the respiratory
and medical ICU settings. Chest 1994;105:1211–6.
[24] Wysocki AB. The effect of intermittent noise exposure on wound healing. Adv Wound Care
1996;9:35–9.
[25] Redwine L, Hauger RL, Gillin JC, et al. Effects of sleep and sleep deprivation on interleu-
kin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab
2000;85:3597–603.
[26] Tochikubo O, Ikeda A, Miyajima E, et al. Effects of insufficient sleep on blood pressure
monitored by a new multibiomedical recorder. Hypertension 1996;27:1318–24.
[27] Kato M, Phillips BG, Sigurdsson G, et al. Effects of sleep deprivation on neural circulatory
control. Hypertension 2000;35:1173–5.
[28] Topf M, Bookman M, Arand D. Effects of critical care unit noise on the subjective quality
of sleep. J Adv Nurs 1996;24:545–51.
[29] Murthy VS, Malhotra SK, Bala I, et al. Detrimental effects of noise on anaesthetists.
Can J Anaesth 1995;42:608–11.
[30] Balogh D, Kittinger E, Benzer A, et al. Noise in the ICU. Intensive Care Med 1993;19:
343–6.
[31] Smith A. A review of the effects of noise on human performance. Scand J Psychol 1989;30:
185–206.
[32] Gabor JY, Cooper AB, Hanly PJ. Sleep disruption in the intensive care unit. Curr Opin Crit
Care 2001;7:21–7.
[33] Freedman NS, Kotzer N, Schwab RJ. Patient perception of sleep quality and etiology of
sleep disruption in the intensive care unit. Am J Respir Crit Care Med 1999;159:1155–62.
[34] Lower JS, Bonsack C, Guion J. Peace and quiet. Nurs Manage 2003;34:40A–40D.
[35] Boivin DB, Duffy JF, Kronauer RE, et al. Dose-response relationships for resetting of
human circadian clock by light. Nature 1996;379:540–2.
[36] Walder B, Francioli D, Meyer JJ, et al. Effects of guidelines implementation in a surgical in-
tensive care unit to control nighttime light and noise levels. Crit Care Med 2000;28:2242–7.
[37] Perras B, Meier M, Dodt C. Light and darkness fail to regulate melatonin release in
critically ill humans. Intensive Care Med 2007;33:1954–8.
[38] Olofsson K, Alling C, Lundberg D, et al. Abolished circadian rhythm of melatonin secre-
tion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand
2004;48:679–84.
474 SALAS & GAMALDO
[39] Tamburri LM, DiBrienza R, Zozula R, et al. Nocturnal care interactions with patients in
critical care units. Am J Crit Care 2004;13:102–12, quiz 114–5.
[40] Celik S, Oztekin D, Akyolcu N, et al. Sleep disturbance: the patient care activities applied at
the night shift in the intensive care unit. J Clin Nurs 2005;14:102–6.
[41] Mortola JP. Breathing around the clock: an overview of the circadian pattern of respira-
tion. Eur J Appl Physiol 2004;91:119–29.
[42] Cooper AB, Gabor JY, Hanly PJ. Sleep in the critically ill patient. Semin Respir Crit Care
Med 2001;22:153–64.
[43] Qureshi A, Lee-Chiong T Jr. Medications and their effects on sleep. Med Clin North Am
2004;88:751–66, x.
[44] Borbely AA, Mattmann P, Loepfe M, et al. Effect of benzodiazepine hypnotics on all-night
sleep EEG spectra. Hum Neurobiol 1985;4:189–94.
[45] Achermann P, Borbely AA. Dynamics of EEG slow wave activity during physiological
sleep and after administration of benzodiazepine hypnotics. Hum Neurobiol 1987;6:
203–10.
[46] Cronin AJ, Keifer JC, Davies MF, et al. Postoperative sleep disturbance: influences of
opioids and pain in humans. Sleep 2001;24:39–44.
[47] Frighetto L, Marra C, Bandali S, et al. An assessment of quality of sleep and the use of
drugs with sedating properties in hospitalized adult patients. Health Qual Life Outcomes
2004;2:17.
[48] Halfens R, Cox K, Kuppen-Van Merwijk A. Effect of the use of sleep medication in Dutch
hospitals on the use of sleep medication at home. J Adv Nurs 1994;19:66–70.
[49] Broughton R, Baron R. Sleep patterns in the intensive care unit and on the ward after acute
myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45:348–60.
[50] Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic
recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed)
1985;290:1029–32.
[51] Buckle P, Pouliot Z, Millar T, et al. Polysomnography in acutely ill intensive care unit
patients. Chest 1992;102:288–91.
[52] Hilton BA. Quantity and quality of patients’ sleep and sleep-disturbing factors in a respira-
tory intensive care unit. J Adv Nurs 1976;1:453–68.
[53] Orr WC, Stahl ML. Sleep disturbances after open heart surgery. Am J Cardiol 1977;39:
196–201.
[54] Kavey NB, Ahshuler KZ. Sleep in herniorrhaphy patients. Am J Surg 1979;138:683–7.
[55] Cooper AB, Thornley KS, Young GB, et al. Sleep in critically ill patients requiring mechan-
ical ventilation. Chest 2000;117:809–18.
[56] Roehrs T, Hyde M, Blaisdell B, et al. Sleep loss and REM sleep loss are hyperalgesic. Sleep
2006;29:145–51.
[57] Zhong X, Hilton HJ, Gates GJ, et al. Increased sympathetic and decreased parasympathetic
cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol
2005;98:2024–32.
[58] Loredo JS, Ziegler MG, Ancoli-Israel S, et al. Relationship of arousals from sleep to sym-
pathetic nervous system activity and BP in obstructive sleep apnea. Chest 1999;116:655–9.
[59] Liu Y, Tanaka H, , Fukuoka Heart Study Group. Overtime work, insufficient sleep, and
risk of non-fatal acute myocardial infarction in Japanese men. Occup Environ Med
2002;59:447–51.
[60] Ayas NT, White DP, Manson JE, et al. A prospective study of sleep duration and coronary
heart disease in women. Arch Intern Med 2003;163:205–9.
[61] Suh SY, Kim JW, Choi CU, et al. Spontaneous coronary dissection associated with sleep
deprivation presenting with acute myocardial infarction. Int J Cardiol 2007;115:e78–9.
[62] Dinges DF, Pack F, Williams K, et al. Cumulative sleepiness, mood disturbance, and
psychomotor vigilance performance decrements during a week of sleep restricted to
4-5 hours per night. Sleep 1997;20:267–77.
[63] Lieberman HR, Bathalon GP, Falco CM, et al. Severe decrements in cognition function
and mood induced by sleep loss, heat, dehydration, and undernutrition during simulated
combat. Biol Psychiatry 2005;57:422–9.
[64] Orton DI, Gruzelier JH. Adverse changes in mood and cognitive performance of house
officers after night duty. BMJ 1989;298:21–3.
[65] Scott JP, McNaughton LR, Polman RC. Effects of sleep deprivation and exercise on
cognitive, motor performance and mood. Physiol Behav 2006;87:396–408.
[66] Caldwell JA, Caldwell JL, Smith JK, et al. Modafinil’s effects on simulator performance
and mood in pilots during 37 h without sleep. Aviat Space Environ Med 2004;75:777–84.
[67] Zohar D, Tzischinsky O, Epstein R, et al. The effects of sleep loss on medical residents’
emotional reactions to work events: a cognitive-energy model. Sleep 2005;28:47–54.
[68] Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance
impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human
regional brain activity. J Sleep Res 2000;9:335–52.
[69] Venkatraman V, Chuah YM, Huettel SA, et al. Sleep deprivation elevates expectation of
gains and attenuates response to losses following risky decisions. Sleep 2007;30:603–9.
[70] Drummond SP, Brown GG, Gillin JC, et al. Altered brain response to verbal learning
following sleep deprivation. Nature 2000;403:655–7.
[71] Drummond SP, Brown GG. The effects of total sleep deprivation on cerebral responses to
cognitive performance. Neuropsychopharmacology 2001;25:S68–73.
[72] Drummond SP, Brown GG, Salamat JS, et al. Increasing task difficulty facilitates the
cerebral compensatory response to total sleep deprivation. Sleep 2004;27:445–51.
[73] Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol
2005;25:117–29.
[74] Stricker JL, Brown GG, Wetherell LA, et al. The impact of sleep deprivation and task
difficulty on networks of fMRI brain response. J Int Neuropsychol Soc 2006;12:591–7.
[75] Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress
disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 1998;26:
651–9.
[76] McGuire BE, Basten CJ, Ryan CJ, et al. Intensive care unit syndrome: a dangerous misno-
mer. Arch Intern Med 2000;160:906–9.
[77] Wilson VS. Identification of stressors related to patients’ psychologic responses to the
surgical intensive care unit. Heart Lung 1987;16:267–73.
[78] Dyer I. Preventing the ITU syndrome or how not to torture an ITU patient! Part 2. Inten-
sive Crit Care Nurs 1995;11:223–32.
[79] Henry WD, Mann AM. Diagnosis and treatment of delirium. Can Med Assoc J 1965;93:
1156–66.
[80] Volicer L, Harper DG, Manning BC, et al. Sundowning and circadian rhythms in
Alzheimer’s disease. Am J Psychiatry 2001;158:704–11.
[81] Martin JL, Marler MR, Harker JO, et al. A multicomponent nonpharmacological inter-
vention improves activity rhythms among nursing home residents with disrupted sleep/
wake patterns. J Gerontol A Biol Sci Med Sci 2007;62:67–72.
[82] Bliwise DL, Carroll JS, Lee KA, et al. Sleep and ‘‘sundowning’’ in nursing home patients
with dementia. Psychiatry Res 1993;48:277–92.
[83] Everson CA, Bergmann BM, Rechtschaffen A. Sleep deprivation in the rat: III. Total sleep
deprivation. Sleep 1989;12:13–21.
[84] Bergmann BM, Everson CA, Kushida CA, et al. Sleep deprivation in the rat: V. Energy use
and mediation. Sleep 1989;12:31–41.
[85] Kushida CA, Bergmann BM, Rechtschaffen A. Sleep deprivation in the rat: IV. Paradoxical
sleep deprivation. Sleep 1989;12:22–30.
[86] Koban M, Swinson KL. Chronic REM-sleep deprivation of rats elevates metabolic rate
and increases UCP1 gene expression in brown adipose tissue. Am J Physiol Endocrinol
Metab 2005;289:E68–74.
476 SALAS & GAMALDO
[87] Rechtschaffen A, Bergmann BM. Sleep deprivation in the rat: an update of the 1989 paper.
Sleep 2002;25:18–24.
[88] Rechtschaffen A, Bergmann BM. Sleep deprivation in the rat by the disk-over-water
method. Behav Brain Res 1995;69:55–63.
[89] Bonnet MH, Arand DL. 24-hour metabolic rate in insomniacs and matched normal
sleepers. Sleep 1995;18:581–8.
[90] Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine
function. Lancet 1999;354:1435–9.
[91] Born J, Lange T, Hansen K, et al. Effects of sleep and circadian rhythm on human circulat-
ing immune cells. J Immunol 1997;158:4454–64.
[92] Vgontzas AN, Zoumakis E, Bixler EO, et al. Adverse effects of modest sleep restriction on
sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004;89:
2119–26.
[93] Shearer WT, Reuben JM, Mullington JM, et al. Soluble TNF-alpha receptor 1 and IL-6
plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy
Clin Immunol 2001;107:165–70.
[94] Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an
inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004;43:678–83.
[95] Ozturk L, Pelin Z, Karadeniz D, et al. Effects of 48 hours sleep deprivation on human
immune profile. Sleep Res Online 1999;2:107–11.
[96] Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immuni-
zation. JAMA 2002;288:1471–2.
[97] Irwin M, McClintick J, Costlow C, et al. Partial night sleep deprivation reduces natural
killer and cellular immune responses in humans. FASEB J 1996;10:643–53.
[98] Dinges DF, Douglas SD, Hamarman S, et al. Sleep deprivation and human immune
function. Adv Neuroimmunol 1995;5:97–110.
[99] Benedict C, Dimitrov S, Marshall L, et al. Sleep enhances serum interleukin-7 concentra-
tions in humans. Brain Behav Immun 2007;21:1058–62.
[100] Haack M, Kraus T, Schuld A, et al. Diurnal variations of interleukin-6 plasma levels
are confounded by blood drawing procedures. Psychoneuroendocrinology 2002;27:
921–31.
Crit Care Clin 24 (2008) 477–491
Pharmacology I: Effects on Sleep

of Commonly Used ICU Medications
Gerald L. Weinhouse, MD
Division of Pulmonary and Critical Care Medicine, Brigham
and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
Critically ill patients are known to have severely disrupted sleep. They
tend to have a paucity of deep sleep (slow-wave and rapid eye movement
[REM] sleep) and a predominance of light sleep and wakefulness [1–7].
Many of the medications commonly used in the ICU have been implicated
in this phenomenon.
Medications can affect sleep in various ways. They may affect the central
nervous system directly by penetration of the blood-brain barrier or indi-
rectly by affecting a medical or psychiatric illness that results in altered sleep
[8]. Some medications may disrupt sleep by their effect on pre-existing sleep
disorders and others have an equally disruptive effect when withdrawn
abruptly [9]. Conversely, medications may have a beneficial effect on sleep
depending on the clinical circumstance [10].
Most medications have been studied for their effect on the electroenceph-
alogram (EEG) and thus the sleep architecture (relative percent of sleep
stages and their orderly progression through the night) of healthy volunteers
(summarized in Table 1). Well-controlled studies of the effects of medica-
tions on sleep have not been done in critically ill patients. What is known
of the effects of some commonly used ICU medications on sleep is reviewed.
Sedatives
The most commonly used ICU sedatives are those that interact with
GABA receptors in the central nervous system. Benzodiazepines and propo-
fol bind at different sites on the receptor but each is able to activate this
inhibitory system to create the altered state characteristic of their clinical ef-
fect [11–13]. GABA activation is part of the endogenous sleep pathway;
however, it is a late event in naturally occurring sleep leaving the early
E-mail address: gweinhouse@partners.org
478 WEINHOUSE
Table 1
Effect of commonly used ICU medications on sleep
Sedatives/hypnotics
Benzodiazepines Y W, REM, SWS, SL
[ TST, Stg II
Propofol Y W, SL
[ TST
a2-agonists (dexmedetomidine) Y SL, REM
[ SWS
Analgesics
Opioids YTST, REM, SWS
[ W, Stg II
NSAID Y TST, SE
Antipsychotics
Typical (haloperidol) Y W, SL
[ SE, Stg II
Atypical (olanzapine) Y W, SL
[ TST, SE, SWS
Antidepressants
Tricyclics Y W, REM
[ TST
SSRIs Y TST, SE, REM
[ W
Trazodone Y W, SL, REM
[ TST, þ/SWS
Cardiovascular
Antihypertensives
b-antagonists [ W, SL
Y REM (variable, depends on lipid solubility)
a2-agonists Y REM
Calcium antagonists NA
ACE inhibitors No effect on sleep
Diuretics NA
Amiodarone Nightmares
Antihypotensives
Epinephrine/norepinephrine Y SWS, REM
Dopamine Y SWS, REM
Respiratory
Xanthines (theophylline) Y TST, SE, REM, SWS
[W
Antiepileptic
Phenytoin Y SL
[ SWS
Barbiturates Y W, SL, REM
[ TST
Carbamazepine Y SL, REM
[ SWS
Valproic acid Y W
[ TST
Gabapentin Y W
[ TST, REM, SWS
(continued on next page)
EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONS 479
Table 1 (continued )
H2-antagonists
Cimetidine? [ SWS
Corticosteroids Y REM, SWS
[ W, Stg II
Substances of abuse
Ethanol Y SL, REM (first half of the night)
[ REM (second half of the night), nightmares
Cannabis Y REM
[ SWS (if acute use; tolerance if long-term use)
Nicotine Y TST, REM
[ SL
Abbreviations: ACE, angiotensin-converting enzyme; NA, not available; NSAID, nonsteroi-
dal anti-inflammatory drug; REM, rapid eye movement; SE, sleep efficiency; SL, sleep latency;
Stg II, stage II sleep; SWS, slow wave sleep; TST, total sleep time; W, wakefulness.
events unaffected [14]. The result is that sleep and conventional sedation
share similarities but also important differences [15]. Table 2 summarizes
the similarities and differences between sedation and naturally occurring
sleep.
At low doses, benzodiazepines and propofol suppress slow-wave sleep
(SWS) and have little effect on REM sleep [16–18]. They shorten sleep la-
tency, decrease arousals, and increase stage II and spindle activity, although
the spindles observed under the influence of sedation are distinct from those
occurring naturally [19]. Higher doses of the medications are associated with
a characteristic slowing of the EEG and both medications can eventually
Table 2
Comparison between sedation and naturally occurring sleep
Sleep Sedation
Differences
Spontaneous Not spontaneous
Circadian Not circadian
Essential function Nonessential function
Reversible with external stimuli Not completely reversible with external stimuli
Associated with decreased NE release Associated with unaffected NE release
from locus ceruleus
Cyclic progression by EEG No cyclic progression by EEG
Similarities
Altered sensorium
Overlapping neurophysiologic pathways
Muscle hypotonia
Temperature dysregulation
Respiratory depression relative
to wakefulness
Abbreviations: NE, norepinephrine; EEG, electroencephalogram.
480 WEINHOUSE
lead to a burst-suppression pattern [20–22]. Both medications are also

associated with alteration of regional cerebral blood flow and metabolism
that may, in part, account for their electrophysiologic effect [23,24].
Investigation into the effects of any drug on sleep is limited by the
absence of reliable measures of sleep quality, especially for critically ill
patients. It is therefore unknown whether these electrophysiologic and met-
abolic effects correspond to important clinical effects. Some animal studies
have suggested that at least one function of sleep, the resolution of objective
measures of sleepiness, is enabled or facilitated during sedation with propo-
fol [25,26]. Further study is necessary to confirm this effect in humans and
also to determine whether other of the functions of sleep may also occur
during sedation.
Dexmedetomidine, an a-agonist, was approved for use in patients initially
mechanically ventilated. Its relationship with sleep is different than that of
the GABA-agonist sedatives owing to effects closer to the onset of the natu-
rally occurring sleep pathway in the central nervous system (CNS) [27]. Dex-
medetomidine is the only parenteral form of this class of drugs available in
the United States, and is believed to inhibit norepinephrine release by locus
ceruleus thus leading to a sequence of events that more closely resembles nat-
ural sleep physiologically and clinically. It is unproven, however, whether
these theoretic advantages offer patients either clinical or outcomes benefits.
Analgesics
Opioids are the mainstay of treatment for pain and discomfort in criti-
cally ill patients. They interact with the natural sleep pathway by way of
the pontothalamic arousal pathway rather than the hypothalamic pathway
most relevant to the sedatives [13,28]. Even single doses of opioids potently
suppress SWS [29,30]. REM sleep suppression by opioids is a dose-depen-
dent phenomenon mediated by the m-receptor [31]. Opioids increase stage
II sleep but also increase wakefulness in healthy volunteers; however, if
pain is a predominant cause of disturbed sleep the overall effects of the opi-
oids would likely be to improve sleep [32].
Even nonsteroidal anti-inflammatory medications can adversely affect
sleep by decreasing sleep efficiency and increasing awakenings. These effects
may be because of inhibition of prostaglandin synthesis, decreased melato-
nin secretion, attenuation of the normal decrease in nocturnal body temper-
ature, or gastric irritation [33,34].
Cardiovascular drugs
Drugs to treat hypertension and arrhythmias
The use of beta-blockers in the ICU has become commonplace with an in-
creasing list of indications for critically ill patients. They are used in the
management of patients who have an acute coronary syndrome, hyperten-

sion, acute burn injuries, and for prophylaxis against dysrhythmias after
cardiothoracic surgery [35–38]. Their effects on sleep are variable and de-
pend on their lipid solubility; it is their ability to cross the blood-brain
barrier that is believed to be related to their central nervous system side
effects. The most lipid soluble (ie, propranolol) have the greatest tendency
to disrupt sleep [39]. They have been found to be associated with night-
mares, insomnia, and REM suppression.
Amiodarone is a highly effective antiarrhythmic drug with neurologic
side effects occurring in up to 40% of patients on a therapeutic dose. These
neurologic effects include insomnia and nightmares in 1% to 3% of non-
critically ill individuals; however, the mechanism of this effect is unknown
[40].
Angiotensin-converting enzyme inhibitors, such as captopril, have not
been found to disturb sleep, and other antihypertensives, such as calcium
antagonists, hydralazine, diuretics, and a1-antagonists such as prazosin,
have not been studied for their effects on sleep [41–44]. a2-agonists, such
as clonidine and methyldopa, can increase total sleep time in healthy sub-
jects but clonidine is REM suppressive and causes vivid dreams, and both
can cause insomnia as an adverse effect [45,46].
Drugs to treat hypotension

Adrenergic receptor agonists may cross the blood-brain barrier under
certain conditions leading to CNS side effects [47]. Septic patients and those
patients simultaneously anesthetized with propofol, for example, may be
more vulnerable to the effects of these drugs on sleep as a consequence of
this phenomenon [48,49]. Norepinephrine and epinephrine likely exert their
effects through direct a1-receptor stimulation, whereas dopamine may affect
the a1-receptor and the D2-receptor. All three agents are associated with
insomnia and the suppression of REM and SWS, although it is likely that
patients sick enough to require these drugs are also under the influence of
other sleep-disrupting variables, such as sepsis, stress, other medications,
and attentive ICU care [9].
Respiratory medications
Patients on mechanical ventilation and those who have acute or chronic
respiratory conditions associated with symptoms are likely to receive at least
inhaled b-adrenergic receptor agonists while in the ICU. CNS stimulation
with associated restlessness and insomnia are well-known adverse effects
of these drugs. The overall effect on sleep may be positive, however, if
they alleviate dyspnea and oxyhemoglobin desaturation, which have been
demonstrated to be associated with arousals from sleep [10,50,51]. In pa-
tients with nocturnal asthma symptoms there may be a subjective
482 WEINHOUSE
improvement with the use of salmeterol, however it is not clear whether

these improvements correspond to objective changes in sleep architecture
[10,52].
Theophylline, a methylxanthine derivative related to caffeine and once
a mainstay in the treatment of asthma and COPD exacerbations, has been
strongly associated with sleep fragmentation, poor sleep efficiency, and
decreased slow-wave and REM sleep [53,54]. Although it may alleviate
nocturnal bronchospasm, the beneficial effects on nocturnal breathing
may not be enough to compensate for the otherwise negative effects on sleep
[55–58].
Corticosteroids
The effects of corticosteroids on sleep may depend on the clinical setting
and the type and dose of the medication administered. Corticosteroids have
been associated with REM suppression and an increase in nocturnal awak-
ening [59]. Their CNS stimulatory adverse effects, the hypomania or ‘‘ste-
roid psychosis,’’ can cause insomnia. Twenty-five percent of healthy
subjects given 80 mg/d of prednisone for 5 days reported decreased sleep
[60].
Gastric acid blockers

The treatment of acute GI bleeding and prophylaxis against stress ulcers
in mechanically ventilated patients includes the use of either histamine type
2 (H2)–receptor antagonists or proton pump inhibitors. The H2-antagonists
are an infrequent cause of insomnia, in part because they have limited CNS
penetrability. Cimetidine, the most blood-brain barrier permeable, is associ-
ated with insomnia in less than 2% of subjects studied, but it may also
increase SWS [61]. Proton pump inhibitors have been less well studied
and only anecdotes of sleep disturbances have been reported.
Antipsychotics
Antipsychotics have become a mainstay of the care of the agitated criti-
cally ill patient. Haloperidol, the most commonly used of the typical
antipsychotics, given to healthy volunteers in a single dose, has recently
been shown to have a tendency to increase sleep efficiency and stage 2 sleep
with little effect on slow-wave activity [62]. Atypical antipsychotics, such as
olanzapine and risperidone, increase total sleep time, sleep efficiency, and
SWS; data on REM effects are not consistent [62,63]. Healthy volunteers
reported improved subjective perception of sleep quality after a dose of
olanzapine and schizophrenics reported improved sleep with risperidone
compared with haloperidol [62,63]; subjective sleep quality has previously
been shown to correlate with SWS [64].
Antidepressants
Although antidepressant therapy may not often be initiated in the ICU,
antidepressants are commonly prescribed in the community and many have
long half-lives; therefore, they are frequently present in critically ill patients
and a potential factor in patients’ care. Because a wide variety of drugs are
prescribed for depression and many patients for whom these drugs are
prescribed already have disturbed sleep, it is difficult to generalize about
the effects of antidepressants on sleep.
The tricyclic antidepressants potently suppress REM sleep but increase
total sleep time and, in general, may improve subjective sleep quality
[65–68]. They increase daytime sedation but this effect lessens with time.
The selective serotonin-reuptake inhibitors (SSRIs) and the dual serotonin
and norepinephrine reuptake inhibitors (ie, venlafaxine) less potently sup-
press REM sleep but decrease total sleep time and may be associated with
insomnia and daytime sedation [69–73].
Trazodone, a selective serotonin and norepinephrine reuptake inhibitor,
is an antidepressant sometimes used to counter the SSRI-induced insomnia.
In fact, it is often used as a hypnotic rather than an antidepressant to cap-
italize on its sedating side effect [65]. It has been shown to increase total
sleep time, shorten sleep latency, have only a minimal inhibitory effect on
REM sleep, and possibly increase SWS in some clinical settings [74–78].
Antiepileptic medications
Most of the older antiepileptic medications, such as phenytoin, pheno-
barbital, valproic acid, and carbamazepine, increase total sleep time and
decrease REM sleep, and some increase SWS [79]. Dose-dependent sedation
is their most common adverse effect with an incidence of 30% to 70% [80].
One of the newer antiepileptics, gabapentin, has been used for various
off-label indications in addition to seizures. It increases total sleep time,
REM sleep, and SWS, and has a reported incidence of daytime sedation
of 5% to 15% [81–83].
Sleep-related withdrawal syndromes of prescribed medications

and addictive drugs
Just as the administration of medications may disturb sleep, the abrupt
cessation of medication may also be disruptive to sleep. Withdrawal
syndromes are likely underdiagnosed; one retrospective study observed
a 32% frequency of acute withdrawal from opioids and benzodiazepines
in mechanically ventilated patients in the ICU more than 7 days [84].
Many medications taken at home are not given in the ICU because they
cannot or should not be administered to an acutely critically ill patient or
because they are believed to be nonessential. Others are given for an acute
484 WEINHOUSE
illness but weaned too quickly. Similarly, substances of abuse (ie, nicotine,
caffeine, alcohol, heroin, cocaine) disrupt sleep both when present and
when withdrawn abruptly.
Medications that are REM suppressive, such as opioids, tricyclic antide-
pressants, serotonin reuptake inhibitors, and benzodiazepines, are associated
with a rebound increase in REM % when withdrawn [8]. This increase in
REM % may be associated with excessive dreaming and nightmares. REM
is also the time of greatest respiratory instability. During REM sleep,
hypoxia may be most severe in those who have COPD and obstructive sleep
apnea (OSA) and apneic events and respiratory variability are likely greater
than at other times during sleep.
Alcohol is often believed to facilitate sleep. In healthy, non–alcohol-
dependent people its presence shortens latency to sleep onset and decreases
REM % during the first half of the night [85,86]. As alcohol is metabolized,
however, there is an increase in REM % during the second half of the night
and an associated increase in sleep fragmentation [87]. Withdrawal from
chronic alcohol use is well known to disrupt sleep with a decrease in total
sleep time and sleep continuity and loss of SWS and REM [88]. Alcohol
further worsens sleep-disordered breathing and snoring and may increase
parasomnias, such as nightmares and night terrors.
Cigarette smoking has been associated with sleep-onset insomnia and
nonrestorative sleep [89]. Nicotine increases alpha activity, which is
Table 3
Effect of drug withdrawal on sleep
Sedatives/hypnotics
Benzodiazepines [ REM %, Y sleep continuity
Analgesics
Opioids Insomnia, [ REM %
Antipsychotics
Haloperidol [ REM latency, [ sleep latency, [ stage II, Y TST
Antidepressants
Tricyclics
SSRI Insomnia, nightmares, excessive dreaming (REM rebound)
Cardiovascular
a2-agonists [ REM %
Antiepileptic
Barbiturates [ REM %, [ sleep latency, Y sleep continuity and TST
H2-antagonists
Cimetidine Insomnia
Stimulants
Amphetamines
Cocaine [ REM %, Y sleep continuity
Substances of abuse
Ethanol Insomnia
Nicotine Insomnia, daytime somnolence
Cannabis [ REM %, Y SWS
Abbreviations: SWS, slow-wave sleep; TST, total sleep time.
characteristic of wakefulness, increases movement, and decreases SWS [90].

Nicotine withdrawal adversely affects sleep continuity [91,92]; however, re-
cent data raise questions about the safety of replacement therapy in critically
ill patients [93]. See Table 3 for withdrawal syndromes associated with these
substances.
Interaction of medication with pre-existing sleep disorders

Some commonly used ICU medications may affect patients’ sleep by their
effect on a pre-existing sleep disorder. Obstructive sleep apnea (OSA) affects
2% to 5% of the population between 30 and 60 years old [94,95] and restless
legs syndrome (RLS) is estimated to affect 5% to 10% of adults [96]. Patients
who have these conditions, whether previously diagnosed or not, are fre-
quently cared for in ICUs.
The relationship between certain medications and OSA is complex. The
REM suppression of such medications as antidepressants might be expected
to improve the sleep of patients who have OSA because REM is the stage
typically associated with the highest respiratory disturbance index and
greatest oxyhemoglobin desaturation. The REM suppression and poor sleep
efficiency observed with these medications, however, does not seem to offer
protection against either the frequency of apneas or desaturations [97]. In
addition, some medications and alcohol are likely to increase upper airway
obstruction in non-intubated patients and should be avoided when possible
Box 1. Effect of drugs on pre-existing sleep disorders

Drugs that worsen airway obstruction in obstructive sleep
apnea
Ethanol
Narcotics
Anesthetics
? Benzodiazepines (data inconclusive at usual hypnotic doses)
? Barbiturates (data inconclusive but known to reduce tone
of the upper airway dilator muscles)
Drugs that worsen PLM/RLS
Tricyclic antidepressants
SSRIs
Lithium carbonate
Dopamine D2 receptor blockers (ie, neuroleptics)
Caffeine
Ethanol
Abbreviation: PLMS, periodic limb movements during sleep.

486 WEINHOUSE
Box 1 [98–104]. See Box 1 for a list of some of the medications which worsen
airway obstruction in patients with OSA.
RLS and the related periodic limb movements during sleep may also be
worsened by medications and alcohol [105,106]. The therapeutic response
of the condition to dopamine agonists is consistent with the finding that
dopamine antagonists worsen it. Box 1 lists some of the medications and
substances of abuse that may worsen RLS/PLMS.
Summary
Most medications commonly used to treat critically ill patients have the
potential to affect sleep by (1) directly or indirectly interacting with the cen-
tral nervous system, (2) acute withdrawal, or (3) worsening a pre-existing
sleep disorder. Poor sleep in the ICU has been linked to at least one adverse
ICU outcome measure [107–111]; therefore, careful scrutiny of the medica-
tions given each patient with attention to optimizing sleep should become an
integral part of patient care.
References
recording of sleep in nine patients receiving postoperative care. BMJ 1985;290:1029–32.
[2] Cooper AB, Thornley KS, Young GB, et al. Sleep in critically ill patients requiring
mechanical ventilation. Chest 2000;117:809–18.
[3] Richards KC, Bairnsfather L. A description of night sleep patterns in the critical care unit.
Heart Lung 1988;17:35–42.
196–201.
[6] Freedman NS, Gazendam J, Levan L, et al. Abnormal sleep/wake cycles and the effect of
environmental noise on sleep disruption in the intensive care unit. Am J Respir Crit Care
Med 2001;163:451–7.
[7] Gabor J, Cooper A, Crombach S, et al. Contribution of the intensive care unit environment
to sleep disruption in mechanically ventilated patients and healthy subjects. Am J Respir
Crit Care Med 2003;167:708–15.
[8] Novak M, Shapiro CM. Drug-induced sleep disturbances: focus on nonpsychotropic
medications. Drug Saf 1997;16(2):133–49.
[9] Bourne RS, Mills GH. Sleep disruption in critically ill patientsdpharmacological consid-
erations. Anaesthesia 2004;59:374–84.
[10] Wiegand L, Mende CN, Zaidel G, et al. Salmeterol vs theophylline: sleep and efficacy
outcomes in patients with nocturnal asthma. Chest 1999;115(6):1525–32.
[11] Bjornstrom K, Eintrei C. The difference between sleep and anaesthesia is in the intracel-
lular signal: propofol and GABA use different subtypes of the GABA(A) receptor beta
subunit and vary in their interaction with actin. Acta Anaesthesiol Scand 2003;47(2):
157–64.
[12] Hales TG, Lambert JJ. The actions of propofol on inhibitory amino acid receptors of
bovine adrenomedullary chromaffin cells and rodent central neurons. Br J Pharmacol
1991;104:619–28.
[13] Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms.
Nature 2005;437:1257–63.
[14] Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by
GABAA receptors in an endogenous sleep pathway. Nat Neurosci 2002;5(10):979–84.
[15] Tung A, Mendelson WB. Anesthesia and sleep. Sleep Med Rev 2004;8:213–25.
[16] Borbely AA, Mattmann P, Loepfe M, et al. Effect of benzodiazepine hypnotics on all-night
sleep EEG spectra. Human Neurobiology 1985;4:189–94.
[17] Achermann P, Borbely AA. Dynamics of EEG slow wave activity during physiological sleep
and after administration of benzodiazepine hypnotics. Hum Neurobiol 1987;6:203–10.
[18] Herregods L, Rolly G, Mortier E, et al. EEG and SEMG monitoring during induction and
maintenance of anaesthesia with propofol. Int J Clin Monit Comput 1989;6:67–73.
[19] Feshchenko VA, Veselis RA, Reinsel RA. Comparison of the EEG effects of midazolam,
thiopental, and propofol: the role of underlying oscillatory systems. Neuropsychobiology
1997;35:211–20.
[20] Hazeaux C, Tisserant D, Vespignani H, et al. Electro-encephalographic changes produced
by propofol. Ann Fr Anesth Reanim 1987;6:261–6.
[21] Harrison AM, Lugo RA, Schunk JE, et al. Treatment of convulsive status epilepticus with
propofol: case report. Pediatric Emergency Care 1997;13:420–2.
[22] Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam
infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57(6):1036–42.
[23] Kajimura N, Nishikawa M, Uchiyama M, et al. Deactivation by benzodiazepine of the
basal forebrain and amygdale in normal humans during sleep: a placebo-controlled
[15O]H2O PET study. Am J Psychiatry 2004;161(4):748–51.
[24] Alkire MT, Haier RJ, Barker SJ, et al. Cerebral metabolism during propofol anesthesia
in humans studied with positron emission tomography. Anesthesiology 1995;82(2):
393–403.
[25] Tung A, Lynch JP, Mendelson WB. Prolonged sedation with propofol in the rat does not
result in sleep deprivation. Anesth Analg 2001;92(5):1232–6.
[26] Tung A, Bergmann BM, Herrera S, et al. Recovery from sleep deprivation occurs during
propofol anesthesia. Anesthesiology 2004;100(6):1419–26.
[27] Nelson LE, Lu J, Guo T, et al. The [alpha]2-adrenoceptor agonist dexmedetomidine
converges on an endogenous sleep-promoting pathway to exert its sedative effect. Anesthe-
siology 2003;98(2):428–36.
[28] Keifer JC, Baghdoyan HA, Lydic R. Sleep disruption and increased apneas after pontine
microinjection of morphine. Anesthesiology 1992;77:973–82.
[29] Shaw IR, Gilles L, Mayer P, et al. Acute intravenous administration of morphine perturbs
sleep architecture in healthy pain-free young adults: a preliminary study. Sleep 2005;28(6):
677–82.
[30] Dimsdale JE, Norman D, DeJardin D, et al. The effects of opioids on sleep architecture.
J Clin Sleep Med 2007;3(1):33–6.
[31] Cronin A, Keifer JC, Baghdoyan HA, et al. Opioid inhibition of rapid eye movement sleep
by a specific mu receptor agonist. Br J Anaesth 1995;74:188–92.
[32] Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine
formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized,
placebo-controlled double-blind trial and an open-label extension trial. J Pain Symptom
Manage 2002;23(4):278–91.
[33] Murphy PJ, Badia P, Myers BL, et al. Nonsteroidal anti-inflammatory drugs affect normal
sleep patterns in humans. Physiol Behav 1994;55:1063–6.
[34] Murphy PJ, Myers BL, Badia P. Nonsteroid anti-inflammatory drugs alter body tempera-
ture and suppress melatonin in humans. Physiol Behav 1996;59:133–9.
[35] Jakobsen CJ, Bille S, Ahlburg P, et al. Perioperative metoprolol reduces the frequency of
atrial fibrillation after thoracotomy for lung resection. J Cardiothorac Vasc Anesth 1997;
11(6):746–51.
488 WEINHOUSE
[36] Urban MK, Markowitz SM, Gordon MA, et al. Postoperative prophylactic administration
of [beta]-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg
2000;90(6):1257–61.
[37] Arbabi S, Ahrns KS, Wahl WL, et al. Beta-blocker use is associated with improved
outcomes in adult burn patients. J Trauma 2004;56:265–71.
[38] Egan BM, Basile J, Chilton RJ, et al. Cardioprotection: the role of beta-blocker therapy.
J Clin Hypertens 2005;7(7):409–16.
[39] McAinsh J, Cruickshank JM. Beta-blockers and central nervous system side effects. Phar-
macol Ther 1990;46:163–97.
[40] Reiffel JA. Intravenous amiodarone in the management of atrial fibrillation. J Cardiovasc
Pharmacol Ther 1999;4:199–204.
[41] Swales JD. ACE inhibitors and the quality of life. J Cardiovasc Pharmacol 1987;9(Suppl):
S22–5.
[42] Materson BJ, Preston RA. Angiotensin-converting enzyme inhibitors in hypertensiond
a dozen years of experience. Arch Intern Med 1994;154:513–23.
[43] Breckenridge A. Angiotensin converting enzyme inhibitors and quality of life. Am J Hyper-
tens 1991;4:79S–82S.
[44] Fletcher AE, Bulpitt CJ, Hawkins CM, et al. Quality of life on antihypertensive therapy:
a randomized double-blind controlled trial of captopril and atenolol. J Hypertens 1990;8:
463–6.
[45] Kanno O, Clarenbach P. Effects of clonidine and yohimbine on sleep in man: polygraphic
study and EEG analysis by normalized slope descriptors. Electroencephalogr Clin Neuro-
physiol 1985;60:478–84.
[46] Gentili A, Godschalk MF, Gheorghiu D, et al. Effect of clonidine and yohimbine on sleep in
healthy men: a double-blind, randomized, controlled trial. Eur J Clin Pharmacol 1996;
50(6):463–5.
[47] Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after
arterial injection. Am J Physiol 1971;221:1629–39.
[48] Myburgh JA, Upton RN, Grant C, et al. The cerebrovascular effects of adrenaline, nor-
adrenaline and dopamine infusion under propofol and isoflurane anaesthesia in sheep.
Anaesth Intensive Care 2002;30:725–33.
[49] Andrzejowski J, Sleigh JW, Johnson IA, et al. The effect of intravenous epinephrine on the
bispectral index and sedation. Anaesthesia 2000;55:761–3.
[50] Fleetham J, West P, Mezon B. Sleep, arousals, and oxygen desaturation in chronic obstruc-
tive pulmonary disease. Am Rev Respir Dis 1982;126:429–33.
[51] Calverley PMA, Brezinova V, Douglas NJ, et al. The effect of oxygenation on sleep quality
in chronic bronchitis and emphysema. Am Rev Respir Dis 1982;126:206–10.
[52] Man GCW, Chapman KR, Ali S, et al. Sleep quality and nocturnal respiratory function
with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD.
Chest 1996;110(3):648–53.
[53] Bailey WC, Richards JM, Manzella BA, et al. Characteristics and correlates of asthma in
a university clinic population. Chest 1990;98:821–8.
[54] Janson C, Gislason T, Boman G, et al. Sleep disturbances in patients with asthma. Respir
Med 1990;84:37–42.
[55] Berry RB, Desa MM, Branum JP, et al. Effect of theophylline on sleep and sleep disordered
breathing in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1991;
143:245–50.
[56] Fitzpatrick MF, Engleman HM, Boellert F, et al. Effect of therapeutic theophylline levels
on the sleep quality and daytime cognitive performance of normal subjects. Am Rev Respir
Dis 1992;145:1355–8.
[57] Martin RJ, Pak J. Overnight theophylline concentrations and effects on sleep and lung
function in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;145:
540–4.
[58] Zwillich CW, Neagley SR, Cicutto L, et al. Nocturnal asthma therapy: inhaled bitolterol
versus sustained-release theophylline. Am Rev Respir Dis 1989;139:470–4.
[59] Born J, Zwick A, Roth G, et al. Differential effects of hydrocortisone, fluocortolone, and
aldosterone on nocturnal sleep in humans. Acta Endocrinol (Copenh) 1987;116:129–37.
[60] Wolkowitz OM, Rubinow D, Doran AR, et al. Prednisone effects on neurochemistry and
behavior: preliminary findings. Arch Gen Psychiatry 1990;47:963–8.
[61] Berlin RG. Effects of H2-receptor antagonists on the central nervous system. Drug Dev Res
1989;17:97–108.
[62] Gimenez S, Clos S, Romero S, et al. Effects of olanzapine, risperidone and haloperidol on
sleep after a single oral morning dose in healthy volunteers. Psychopharmacology 2007;190:
507–16.
[63] Yamashita H, Morinobu S, Yamawaki S, et al. Effect of risperidone on sleep in schizophre-
nia: a comparison with haloperidol. Psychiatry Res 2002;109:137–42.
[64] Akerstedt T, Hume K, Minors D, et al. Good sleepdits timing and physiological sleep
characteristics. J Sleep Res 1997;6:221–9.
[65] Gursky JT, Krahn LE. The effects of antidepressants on sleep: a review. Harv Rev Psychi-
atry 2000;8:298–306.
[66] Armitage R. Effects of antidepressant treatment on sleep EEG in depression. J Psychophar-
macol 1996;10(Suppl 1):22–5.
[67] Dunleavy DL, Brezinova V, Oswald I, et al. Changes during weeks in effects of tricyclic
drugs on the human sleeping brain. Br J Psychiatry 1972;120:663–72.
[68] Nicholson AN, Pascoe PA, Turner C. Modulation of sleep by trimipramine in man. Eur
J Clin Pharmacol 1989;37:145–50.
[69] Nicholson AN, Pascoe PA. Studies on the modulation of the sleep-wakefulness continuum
in man by fluoxetine, a 5-HT uptake inhibitor. Neuropharmacology 1988;27:597–602.
[70] Von Bardeleben UV, Steiger A, Gerken A, et al. Effects of fluoxetine upon pharmacoendo-
crine and sleep-EEG parameters in normal controls. Int Clin Psychopharmacol 1989;
4(Suppl 1):1–5.
[71] Hendrickse WA, Roffwarg HP, Grannemann BD, et al. The effects of fluoxetine on the
polysomnogram of depressed outpatients: a pilot study. Neuropsychopharmacology
1994;10:85–91.
[72] Kerkhofs M, Rielaert C, DeMaertelaer V, et al. Fluoxetine in major depression: efficacy,
safety and effects on sleep polygraphic variables. Int Clin Psychopharmacol 1990;5:253–60.
[73] Staner L, Kerkhofs M, Detroux D, et al. Acute, subchronic and withdrawal sleep EEG
changes during treatment with paroxetine and amitriptyline: a double-blind randomized
trial in major depression. Sleep 1995;18:470–7.
[74] Van Bemmel AL, Havermans RG, Van Diest R. Effects of trazodone on EEG sleep and
clinical state in major depression. Psychopharmacology (Berl) 1992;107:569–74.
[75] Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone
in depressed insomniac patients. J Clin Psychiatry 1990;51(Suppl):13–7.
[76] Mouret J, Lemoine P, Minuit MP, et al. Effects of trazodone on the sleep of depressed
subjectsda polygraphic study. Psychopharmacology (Berl) 1988;95(Suppl):S37–43.
[77] Ware JC, Pittard JT. Increased deep sleep after trazodone use: a double-blind placebo-
controlled study in healthy young adults. J Clin Psychiatry 1990;51(Suppl):18–22.
[78] Montgomery I, Oswald I, Morgan K, et al. Trazodone enhances sleep in subjective quality
but not in objective duration. Br J Clin Pharmacol 1983;16:139–44.
[79] Wolf P, Roder-Wanner UU, Brede M. Influence of therapeutic phenobarbital and phenyt-
oin medication on the polygraphic sleep of patients with epilepsy. Epilepsia 1984;25:
467–75.
[80] Malow BA, Bowes RJ, Lix X. Predictors of sleepiness in epilepsy patients. Sleep 1997;20:
1105–10.
[81] Brazil CW. Effects of antiepileptic drugs on sleep structure: are all drugs equal? CNS Drugs
2003;17:719–28.
490 WEINHOUSE
[82] Sammaritano M, Sherwin A. Effect of anticonvulsants on sleep. Neurology 2000;54:

S16–24.
[83] Foldvary-Schaefer N, DeLeon SI, Karafa M, et al. Gabapentin increases slow-wave sleep in
normal adults. Epilepsia 2002;43:1493–7.
[84] Cammarano WB, Pittet JF, Weitz S, et al. Acute withdrawal syndrome related to the ad-
ministration of analgesic and sedative medications in adult intensive care unit patients.
Crit Care Med 1998;26(4):676–84.
[85] Yules RB, Lippman ME, Freedman DX. Alcohol administration prior to sleep: the effect of
EEG sleep stages. Arch Gen Psychiatry 1967;16:94–7.
[86] Lobo LL, Tufik S. Effects of alcohol on sleep parameters of sleep-deprived healthy volun-
teers. Sleep 1997;20:52–9.
[87] Madsen BW, Rossi L. Sleep and Michael-Menten elimination of ethanol. Clin Pharmacol
Ther 1980;27:114–9.
[88] Kotorii T, Nakazawa Y, Yokoyama T. Terminal sleep following delirium tremens in
chronic alcoholics: polysomnographic and behavioral study. Drug Alcohol Depend 1982;
10:125–34.
[89] Wetter DW, Young TB. The relation between cigarette smoking and sleep disturbance.
Prev Med 1994;23:328–34.
[90] Davila DG, Hurt RD, Offord KP, et al. Acute effects of transdermal nicotine on sleep
architecture, snoring, and sleep-disordered breathing in nonsmokers. Am J Respir Crit
Care Med 1994;150:469–74.
[91] Wolter TD, Hauri PJ, Schroeder WJ, et al. Effects of 24-hour nicotine replacement on sleep
and daytime activity during smoking cessation. Prev Med 1996;25:601–10.
[92] Hughes JR, Higgins ST, Bickel WK. Nicotine withdrawal versus other drug withdrawal
syndromes: similarities and dissimilarities. Addiction 1994;89:1461–70.
[93] Lee AH, Afessa B. The association of nicotine replacement therapy with mortality in
a medical intensive care unit. Crit Care Med 2007;35(6):1517–21.
[94] Kripke DF, Ancoli-Israel S, Klauber MR, et al. Prevalence of sleep-disordered breathing in
ages 40-64 years: a population-based survey. Sleep 1997;20:65–76.
[95] Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among
middle-aged adults. N Engl J Med 1993;328:1230–5.
[96] Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic
features. J Clin Neurophysiol 2001;18:128–47.
[97] Smith SS, Dingwall K, Jorgenson G, et al. Associations between the use of common
medications and sleep architecture in patients with untreated obstructive sleep apnea.
J Clin Sleep Med 2006;2(2):156–62.
[98] Collop NA. Medroxyprogesterone acetate and ethanol-induced exacerbation of obstruc-
tive sleep apnea. Chest 1994;106:792–9.
[99] Scrima L, Broudy M, Nay KN, et al. Increased severity of obstructive sleep apnea after
bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep
1982;5:318–28.
[100] Taasan VC, Block AJ, Boysen PG, et al. Alcohol increases sleep apnea and oxygen desatu-
ration in asymptomatic men. Am J Med 1981;71:240–5.
[101] Dolly FR, Block AJ. Effect of flurazepam on sleep-disordered breathing and nocturnal
desaturation in asymptomatic subjects. Am J Med 1982;73:239–43.
[102] Mendelson WB, Garnett D, Gillin JC. Flurazepam-induced sleep apnea syndrome in
a patient with insomnia and mild sleep-related respiratory changes. J Nerv Ment Dis
1981;160:261–4.
[103] Cately DM, Thornton C, Jordan C, et al. Pronounced episodic oxygen desaturation in
the postoperative period: its association with ventilatory pattern and analgesic regimen.
Anesthesiology 1985;63:20–8.
[104] Robinson RW, Zwillich CW, Bixler EO, et al. Effects of oral narcotics on sleep-disordered
breathing in healthy adults. Chest 1987;91:197–203.
[105] Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days
of venlafaxine administration in normal volunteers. J Clin Psychiatry 1997;58:348–50.
[106] Aldrich MS, Shipley JE. Alcohol use and periodic limb movements of sleep. Alcohol Clin
Exp Res 1993;17:192–6.
[107] Noaves MA, Knobel E, Bork AM, et al. Stressors in ICU: perception of the patient, rela-
tives and health care team. Intensive Care Med 1999;25:1421–6.
[108] Rotondi AJ, Lakshmipathi C, Sirio C, et al. Patients’ recollections of stressful experiences
while receiving prolonged mechanical ventilation in an intensive care unit. Crit Care Med
2002;30:746–52.
[109] Nelson JE, Meier DE, Oei EJ, et al. Self-reported symptom experience of critically ill cancer
patients receiving intensive care. Crit Care Med 2001;29:277–82.
[110] Freedman N, Kotzer N, Schwab R. Patient perception of sleep quality and etiology of sleep
disruption in the intensive care unit. Am J Respir Crit Care Med 1999;159:1155–62.
[111] Simini B. Patients’ perceptions of intensive care. Lancet 1999;354:571–2.
Crit Care Clin 24 (2008) 493–515
Effects of Common Medications

Used for Sleep Disorders
Qanta A. Ahmed, MD, FCCP, FAASM
Division of Pulmonary, Critical Care, Sleep and Allergy Medicine,
Medical University of South Carolina, Clinical Science Building Suite 812,
96 Jonathan Lucas Street, Charleston, SC 29425, USA
Americans are sleep deprived and sleep disordered. Recent estimates

suggest 47 million Americans, including infants, children, and adolescents,
may be affected [1]. Czeisler identifies ‘‘sleep machismo’’ (in which sleep is
considered an expendable luxury rather than a biologic need) as a major
contributing factor to sleep deprivation [2] in the United States. Of the
more than 30% of Americans who report sleep complaints, nearly half re-
port chronic insomnia [3]. Sleep disorders are often comorbid or exacer-
bated by chronic disease [4].
Awareness of clinical sleep disorders is finally increasing, reflected in in-
creasing efforts to develop new treatments [5] and expanding programs
across the United States to train dedicated sleep practitioners. Additionally,
intensified direct-to-consumer advertising programs have encouraged
patients to seek attention for sleep dissatisfaction, often for the first time.
Sleep is affected by medical conditions and the therapies used to treat them;
certain conditions (eg, fibromyalgia) are now being treated by altering sleep
architecture [6], albeit using off-label strategies, with encouraging results.
Sleep disorders encompass the parasomnias, hypersomnias, and dyssom-
nias, and movement disorders (which, although strictly disorders of wake-
fulness, can affect sleep), but insomnia is the most prevalent sleep disorder
requiring pharmacotherapy. The prime focus of this article is therefore
the agents used to treat insomnia. There is a new philosophy to approaching
patients who have insomnia: that insomnia is a chronic disorder that needs
to be managed with careful pharmacotherapy (among other treatments)
rather than a troublesome symptom that needs to be palliated over the short
Disclosure: Dr. Ahmed has been the recipient of speakers bureau fees for ramelteon and
pramipexole.
E-mail address: qanta.ahmed@gmail.com
494 AHMED
term; discussion of new trends in treatment strategies is indicated. This dis-

tinction of insomnia as a disorder has been clearly identified in the recent
National Institutes of Health (NIH) State of the Science Panel in June
2005 [7,8] and has lead to the newer US Food and Drug Administration
(FDA) approvals for long-term prescriptions of hypnotics. These changing
attitudes contribute greatly to encouraging clinicians and patients alike to
overcome the enormous stigma of seeking treatment of insomnia.
Additional attention is devoted in this article to current treatments for
restless leg syndrome and the specific roles for modafinil (a wake-promoting
stimulant) and sodium oxybate, both unique agents with specific indications.
By the end of the article the non–sleep specialist intensivist will be famil-
iarized with those unregulated, regulated but off-label, and FDA-indicated
sleep agents most likely encountered in patients under his or her care in
today’s critical care arena. Discussion of some commonly occurring associ-
ations, including parasomnias in the setting of hypnotic use, is included.
Unregulated agents
Patients who sleep poorly often self-medicate before seeking consulta-
tion. Among Americans, the most common agent used as self-medication
for insomnia is alcohol, taken by 6% to 13% [9] of the population as a sleep
aid. In a population with acute insomnia however, this increases to 15% to
28% [3,9,10], and in women who have symptomatic insomnia this increases
to 70% in those older than age 85 [10,11]. Specific inquiry should always be
made concerning the use of alcohol as a sleep aid, rather than merely in units
per week. Many patients do not recall their use of alcohol to promote sleep
and do not volunteer this history otherwise.
It is unsurprising, therefore, that Americans also resort to unregulated
health supplements to improve sleep, including valerian, melatonin, hops,
lavender, passion flower, kava-kava, and skullcap [12]. In the United States
these substances are classified as herbal or dietary supplements and are not
subject to rigorous FDA regulation. Although considered safe by much of
the public, their exact components and concentrations remain unknown,
as does the potential for serious adverse effects. Clinicians are advised to
avoid recommending their use. Certain agents, including kava-kava and
melatonin supplements, have been implicated in liver toxicity, and in the
case of kava-kava the FDA has issue a warning. The NIH State of the Sci-
ence symposium, which met in June 2005, specifically counsels against the
use of these agents for insomnia based on insufficient efficacy data [8,13].
The practitioner is wise to discourage their use in the patient population.
Regulated commonly used over-the-counter sleep aids

When obtaining a medication history patients often overlook their over-
the-counter (OTC) medications. Specific inquiry should be made of patients
EFFECTS OF COMMON MEDICATIONS 495
about OTC purchases to promote sleep. Most of these preparations include

diphenhydramine as the active ingredient, although some contain doxyl-
amine instead [14]. These agents are initially sedating but quickly produce
tolerance and their longer half-lives allow accumulation to lead to daytime
negative consequences described by patients as ‘‘hangover’’ effect [14]. Care
must be taken to teach the patient to avoid adding these medications to exist-
ing anticholinergic medicines, which could result in additive postsynaptic
muscarinic blockade producing troublesome dry mouth, blurring of vision,
urinary retention, constipation, and even confusion or delirium. To clarify
their undesirability as sleep aids, the NIH consensus panel discussing chronic
insomnia advised against their use as sleep aids on the basis of lack of efficacy
data and concerns about their individual or additive adverse effects [7,14].
Commonly used off-label prescription medication

Several medications are often ordered by the physician community for
the management of insomnia, without specific FDA indications for their
use as sleep aids. FDA indications are commonly withheld for these agents
because of a lack of clinical trial data explicitly assessing their efficacy in
measured primary sleep endpoints and paucity of other clinical data sup-
porting their use. Nonetheless, prescribing patterns are difficult to change
and clinicians must be aware that certain classes of agents are ordered
only for hypnotic effect.
Several classes of psychotropic medications are used in this manner, fore-
most of which is trazodone [15], a sedating antidepressant. A review of
prescribing habits in the Unite States revealed that three of the four most
commonly prescribed agents for promoting sleep were antidepressants
ordered off FDA label: trazodone, amitriptyline, and mirtazapine [15].
This finding is worrisome on several fronts. Not only have these medications
not been tested to assess their impact on insomnia, they are mostly pre-
scribed by non–sleep practitioners who considered them tried and tested,
relatively benign medicines, although they carry several important side
effects. These can range from unwanted daytime sedation to orthostatic
hypotension, arrhythmias, and unpleasant anticholinergic effects. Specifi-
cally, trazodone also carries the risk for priapism and could complicate
serotoninergic syndrome when inadvertently combined with serotonergic
medications. There may be a segment of patients taking these sedating an-
tidepressants who do improve after initiation but only because of a likely
coexisting affective disorder comorbid to their insomnia. The NIH State
of the Science panel on chronic insomnia in June 2005 clearly discouraged
their use for primary treatment of insomnia and this recommendation
should be reinforced. Critical care physicians attending patients who may
be on these medications before presenting to the ICU should specifically
question whether these drugs were ordered for off-label indications, and if
so suggest appropriate alternatives after the critical illness has resolved [7,8].
496 AHMED
Food and Drug Administration–approved hypnotic medications

Although practice patterns are slow to change, the armamentarium avail-
able to treat insomnia is growing, which benefits the patient, the practitioner
at the bedside, and the basic and clinical science researchers who begin to
unlock the elusive mechanisms of sleep onset and maintenance through
each novel emerging compound. This section focuses predominantly on
the benzodiazepine receptor agonist (BZRA) and the melatonin receptor
agonist classes.
Benzodiazepine receptor agonists

Benzodiazepines first became available in the 1960s and by the 1970s were
prescribed for insomnia with the arrival of flurazepam. Since then, agents
that also occupy the benzodiazepine receptor have been developed, and ex-
ert an array of effects differing in varying degrees from the original benzo-
diazepines. They are listed in Table 1.
These agents share common pharmacodynamic properties. It is useful to
review the structure of the benzodiazepine receptor itself, which has extra-
cellular, cell membrane, and intracellular components.
The g-aminobutyric acid receptor: structure and activation

The BZRA medications function as positive allosteric modulators of the
pentameric g-aminobutyric acid (GABAA) receptor, increasing its perme-
ability to the chloride ion through a central ion channel. This increase of
Table 1
US Food and Drug Administration–approved hypnotic agents
Medication Half-life (h) Dose (mg)
Benzodiazepine receptor agonist (BZRA)
Immediate-release BMZ
Estazolam 8–24 1 and 2
Flurazepam 48–120 15 and 30
Quazepam 48–120 7.5 and 15
Temazepam 8–20 7.5, 15, 22.5, and 30
Triazolam 2–4 0.125 and 0.25
Immediate-release non-BMZ
Eszopiclone 5–7 1, 2, and 3
Zaleplon 1 5 and 10
Zolpidem 1.5–2.4 5 and 10
Modified-release non-BMZ
Zolpidem ER 2.8–2.9 6.25 and 12.5
Selective melatonin receptor agonist
Ramelteon 1–2.6 8
All agents except ramelteon are controlled schedule IV substances.
Data from Neubauer DN. The evolution and development of insomnia pharmacotherapies.
J Clin Sleep Med 2007;3(Suppl 5):S11–5.
intracellular chloride levels because of binding to the GABA receptor in-

creases transmembrane polarity and makes the occurrence of an action po-
tential more difficult, inhibiting cellular firing. GABA agonists are therefore
inhibitory.
Usually the GABA receptor is made of two beta, two alpha, and one
gamma subunit. The GABA agonist medications have a site of recognition
nestling in the groove between the alpha and gamma subunit in the GABAA
receptor. GABA is the most disseminated inhibitory central nervous system
(CNS) neurotransmitter and exerts several effects, including anxiolysis, mus-
cle relaxation, anticonvulsant properties, and hypnosis. Different BZRA
medicines exert these effects to various degrees; however, specific targeting
of the ventrolateral preoptic nucleus (a center involved in coordinating sleep
and wakefulness) is probably the most significant site of drug action in the
BZRA class [12].
Several distinct GABA receptors have been identified in recent years, in-
cluding GABAA, GABAB, and GABAC, and they are configured in several
patterns. The receptors differ in the gating mechanism of their central chan-
nel: subtypes A and C are ligand gated, whereas subtype B is G-protein cou-
pled [16,17].
Alpha subunit selectivity: clinical relevance

Important distinctions between the BZRA agents are determined by the
degree of GABAA receptor specificity: the higher the selectivity for GABAA
the better tolerated the medication, with reduced adverse effects and compar-
atively reduced rebound insomnia on withdrawal of the agent. This GABAA
selectivity is demonstrated by the newer agents, including zaleplon, zolpidem,
and eszopiclone, whereas traditional benzodiazepines do not selectively bind
to the alpha subunit, binding also to other subunits. Improved ability to
remove the medication without eliciting intense rebound insomnia is less
likely to result in dependence, a major concern in long-term hypnotic use.
Pharmacokinetics
BZRA medicines are rapidly absorbed and all reduce sleep latency1 (time
taken to fall asleep). The duration of action depends on the half-life of the
agent, which, as shown in Table 1, is widely variable. The non-BZRAs
tend to have shorter half-lives, certainly much improved over the pioneering
benzodiazepines that were associated with deleterious daytime effects
because of the ongoing bioavailability of prolonged half-lives, some lasting
several days. Longer half-lives are more likely to help with sleep maintenance,
although zaleplon, with its extremely short half-life of 1 hour, is often ordered
1
For a normal adult this is considered up to 20 minutes, usually falling in the realm of
10 to 20 minutes.
498 AHMED
specifically for nocturnal awakenings and may be taken serially for nocturnal
awakenings (no more than 20 mg in a 24 hour period for a healthy adult).
Recently extended-release agents (modified release zolpidem) have been
approved for use in chronic insomnia on the premise that release is sustained
gradually as the major sleep period progresses while avoiding aftereffects on
the subsequent day. Other agents are in development.
Principles for prescribing benzodiazepine receptor agonists

In general, several habits are well advised when initiating BZRA therapy.
It is useful to establish a reliable relationship with the patient so that the
clinician can be confident the patient will return for review of medication
impact and follow some simple complementary recommendations for the
treatment of insomnia. A sensible approach is to meet with the patient to
investigate possible causes for insomnia and then to agree that the patient
will complete a sleep diary to provide a longitudinal view of the patient’s
sleep–wake routine. On the patient’s return the clinician can be more secure
knowing the patient is compliant and likely to provide useful feedback
during the initiation of therapy.
New sleep medications should generally be commenced when the patient
has no commitments early the next morning. For a person who works dur-
ing the week, a Friday evening would be a good time to start. The patient
should be instructed to take the medication 15 minutes before desired sleep
time, rather than ‘‘bedtime,’’ because many patients enter the bed for non–
sleep-related recreation (including snacking or television watching) hours
before sleep is desired. No alcohol should be combined with any agent. Offer
the patient the option to skip the sleep aid on the night of alcohol ingestion
in the event of a social event. The minimum effective dose should be used; in
a new patient this would suggest the smallest clinical dose should be
commenced and titrated upward over time under direct supervision [18].
Adverse events with benzodiazepine receptor agonist use

Benzodiazepine receptor blockers are usually well tolerated but several
concerns are pertinent. Dependency, withdrawal, and tolerance are of great-
est concern and these fears often influence practitioners away from prescrib-
ing an FDA-approved agent in place of an off-label treatment option.
Patients also often express fears and may defer seeking treatment of insom-
nia because of this.
The World Health Organization defines drug dependency as follows: an
abnormal state, leading to psychic and sometimes also a physical dependence
‘‘resulting from the interaction between a living organism and a drug charac-
terized by behavioral and other responses that always include a compulsion to
take the drug on a continuous or a periodic basis to experience its psychic
effects, and sometimes avoid the discomfort of its absence’’ [19]. Many studies
examining dependence with the use of BZRA medications differ in their
research definitions of dependence making comparisons of the data difficult,

but the most consistently applied definitions include the presence of specific
withdrawal syndromes or symptoms after removal of the drug. Withdrawal
is also defined differently by research groups.
With benzodiazepine use dependency is possible after withdrawal of ther-
apeutic doses of the agent [20,21] and some data suggest up to 10% to 30%
of individuals using the medications chronically may demonstrate depen-
dence [22]. Long-term use, higher doses, and higher potency have been
related to increased risk for dependence [23]. Alcoholism, personality
disorders, and use without medical supervision are also suggested as major
risk factors for dependence [23]. These observations lend support to careful
patient selection, use of the minimum clinically effective dose, and frequent
outpatient follow-up while on the medication as sensible strategies whenever
prescribing these agents. Other important adverse effects can include head-
ache, nausea, diarrhea, next-day somnolence, and anterograde amnesia.
Patients should always be informed to allow at least 7 to 8 hours total sleep
time after ingestion as a means to avoid early morning sleepiness. Rarely,
patients can demonstrate confusional arousals with complicated behaviors
occurring a few hours after sleep onset following drug ingestion, including
sleep-related eating syndrome [24,25], warranting discontinuation.
In sum, careful patient selection can reduce risk for dependency, which is
a function of not only the drug but also the user. Not all patients on BZRA
hypnotics become dependent, and fears of dependence should not preclude
use of the agents in appropriate settings.
Melatonin receptor agonists

In 2005, the FDA approved a new class of agents to be used as hypnotics:
the selective melatonin receptor agonists. This was the first new class of
agents to be approved for hypnotic use in several decades. Presently only
one formulation is FDA approved for use, ramelteon, but others are in
development. In marked contrast to the aforementioned drugs, ramelteon
promotes sleep without cognitive or psychomotor impairment or any abuse
liability [26–30]. It is therefore the only unscheduled hypnotic currently
available. The remaining hypnotics are all controlled scheduled class IV
agents because of their abuse potential.
Melatonin 1 and melatonin 2 receptors

Melatonin (N-acetyl 5-methoxytryptamine) is the major neurohormone
of the pineal gland and is often described as the hormone of darkness
[31]. It plays a pivotal role in circadian rhythmicity [31] and prepares the
brain for sleep onset. Melatonin synthesis and release in the pineal gland
are inhibited by light exposure and stimulated by darkness. This synchrony
500 AHMED
to the external environment, called entrainment, occurs through the retino-

hypothalamic tract, which links photoreceptors in the retina to the supra-
chiasmatic nucleus (SCN), which is a condensation of projections situated
just above the optic chiasm [32,33]. This SCN is the body’s internal pace-
maker to all circadian rhythms.
Melatonin levels oscillate in a circadian rhythm and in humans the noc-
turnal increase in melatonin starts after the onset of darkness, known as the
dim light melatonin onset (DLMO), usually peaking in the early hours of
the night between 2 and 4 AM, after which levels gradually dissipate during
the remainder of night [34]. These rhythms originating in the SCN are
closely entrained to external cues, light being the most potent entrainer of
all. The SCN activity thus parallels ambient cycles of light and darkness
[35,36]. When these timings are deranged relative to the chronologic clock
disorders may arise, including time zone change (jet lag).
Melatonin receptors and regulation of the sleep–wake cycle

Melatonin exerts physiologic effect through two G-protein coupled recep-
tors that are concentrated in the SCN, the melatonin 1 receptor (MT1) [37]
and the melatonin 2 receptor (MT2) [38]. Although the receptors are also
found in the periphery, their activation centrally exerts specific effects on
sleep. Activation of MT1 reduces SCN firing rates [39] and inhibits the alert-
ing signal from the SCN, promoting sleep onset. Activation at the MT2
receptor influences advance shifts the phase of the circadian rhythm [39],
rendering the peak secretion of DLMO earlier and also promoting sleep
onset. Agents acting at the MT1 and MT2 receptor thus have two effects:
hypnotic and phase shifting.
MT3 receptors also exist but are found more diffusely in the brain and
other organs: lungs, heart, liver, and kidneys [39]. Their function is unclear
at present but may involve the control of intraocular pressure and inflamma-
tory responses in the microcirculation [40]. Melatonin has also been found
to induce sedation and lower core body temperature, a vital prerequisite
for sleep onset [41–45].
Ramelteon
Selectivity for binding to MT1 and MT2 receptors over binding to MT3
receptors is 1000-fold greater in ramelteon when compared with melatonin
[46]. Ramelteon therefore acts specifically on the SCN through this receptor
specificity. It is rapidly absorbed reaching peak concentrations within an
hour of ingestion [12]. Patients are therefore advised to take the medication
within 30 minutes of desired sleep onset. Mean elimination half-life is 0.8 to
2.6 hours and because of extensive first-pass metabolism less than 2% of the
total dose remains bioavailable after ingestion of a single oral dose of 16 mg
[47–49].
The recommended dose is 8 mg [50]. In a study with a carefully de-

fined population with primary insomnia for at least 3 months, ramelteon
at 8 mg was compared with placebo with daily use for a 35-day period.
Latency to persistent sleep was measured on polysomnography in a sleep
laboratory on week one, week three, week five, and week six. At the end
of the study all patients received two nights of placebo to assess rebound
insomnia [51]. Statistically significant reductions in latency to persistent
sleep (ranging from 53 minutes to 58.7 minutes [51]) were seen in the
ramelteon group as early as week one but persisting at week five and
no rebound insomnia was noted on withdrawal of the drug. No signifi-
cant next-day effects were reported. The drug was also well tolerated
and without notable difference when compared with placebo other than
somnolence (5% versus 3% for placebo), dizziness (5% versus 3% for
placebo), and fatigue (4% versus 2% for placebo).
Ramelteon’s metabolism depends primarily on cytochrome P1A2 [50];
therefore ramelteon should not be used with fluvoxamine, which is a cyto-
chrome P1A2 inhibitor that could potentially severely increase its bioavail-
ability and cause excess sedation. Other less-potent inhibitors of cytochrome
P1A2 should also be used in combination with caution. Finally, long-term
nightly administration of ramelteon has been found to increase serum
prolactin levels [52] and decrease testosterone levels [53] but the clinical
relevance of this remains unknown.
In summary, melatonin has central importance in the timing and arrival
of sleep onset and selective drugs binding to the receptors gating these phys-
iologic processes have therapeutic roles in treating insomnia, particularly
sleep-onset insomnia. Future applications to specifically manipulate timing
of the sleep phase may also exist and other agents, including LY 156735
and VEC-162, are currently under investigation. Selective MT1 and MT2
agonists offer attractive alternatives to the existing armamentarium and
although consensus treatment guidelines are not in existence, they do offer
the option of combination treatments tailored to specific patients.
Sodium oxybate
Sodium oxybate is the sodium salt of g-hydroxybutyrate (GHB)2 and is
a unique drug with specific applications in the management of narcolepsy,
for which it is FDA indicated. Narcolepsy is a rare socially disabling
disorder of excessive hypersomnolence affecting approximately 1 in 2000
Americans. Daytime sleepiness in this disorder coexists with several other
2
GHB is the name of the molecule and is widely used in the literature. Sodium oxybate
is the official generic term for the pharmaceutical agent marketed by Jazz Pharmaceuticals.
In many references these terms are used interchangeably.
502 AHMED
associations, including hypnagogic hallucinations,3 sleep paralysis,4 and in

some patients, cataplexy.5 Other uses of the medication are emerging, and
although off label, the literature does suggest a helpful role in the manage-
ment of fibromyalgia [54,55].
Sodium oxybate is a white crystalline powder that is readily soluble in
aqueous bases and rapidly absorbed in liquid form. Initially in the United
States, GHB became available widely in health food shops, fitness centers,
and bodybuilding gymnasiums during the 1980s largely because of reports
of associated increases in growth hormone related to drug intake (see later
discussion) [56]. It was also touted as a weight-loss agent and insomnia rem-
edy. With the widespread availability of the drug on the Internet in the
1990s recreational consumption exploded and eventually the molecule
gained notoriety as the ‘‘date rape drug,’’ associated with all-night rave
parties [57] where it was widely exchanged for its intoxicant properties
[57]. Combining it with alcohol lead to increasing numbers of emergency
admissions for altered consciousness, respiratory depression, and sexual
assault [58]. Now it is modified by an additional sodium molecule append-
age as manufactured by Jazz Pharmaceuticals specifically because the
sodium molecule affords the drug a strongly salty taste, making the spiking
of drinks surreptitiously with the substance difficult.
Pharmacology
GHB likely has several distinct but overlapping pharmacologic effects
involving several receptor systems [59]. GHB is a naturally occurring metab-
olite produced in the CNS (brain) and other mammalian tissues. It is most
concentrated in the hypothalamus and basal ganglia. More specifically
dopaminergic areas, such as the substantia nigra and the ventral tegmental
area, contain high concentrations of GHB, suggesting that GHB may atten-
uate dopamine expression (the neurotransmitter of wakefulness). Its role is
suggested to be neuromodulation or neurotransmission particularly with
the discovery of specific recognition sites in the CNS for this molecule
[60,61]. It is less likely, therefore, to be simply a degradation metabolite
of g-aminobutyric acid, as previously believed [60,61]. In specific
3
Hallucinating dream content at the borders of sleep onset.
4
The inability to willfully move usually legs and sometimes arms also at sleep onset at-
tributable to transient atonia. Sometimes this can become frightening and lead to sleep onset
insomnia or sleep avoidance. Episodes are associated with anxiety and palpitations, and ter-
minated with intense effort or an extraneous stimulus, such as a phone ringing or hearing
one’s name called.
5
A sudden bilateral loss of postural skeletal muscle tone triggered usually by a strong
positive emotion. Full body collapse may result mimicking syncope or a seizure, or findings
may be more subtle, such as a head rolling forward or jaw sagging or the need to lean
against a wall. These findings represent an intrusion of REM sleep–related muscle atonia
into wakefulness. The patient is awake during these episodes.
concentrations GHB also acts as a GABAB receptor agonist. Additionally

pharmacologic doses of GHB increase serotonin turnover and interact
with the endogenous opioid system. GHB is being used off label for the
management of chronic painful disorders as reflected in recent literature.
Pharmacodynamics
Sodium oxybate is rapidly absorbed in oral solution with bioavailability
estimated to be 25%. Average time to peak plasma concentration ranges
from 0.5 to 1.25 hours and plasma half-life is 40 to 60 minutes. Treating
narcolepsy requires an initial bedtime dose followed by a repeat dose 2.5
to 4 hours later to ensure plasma concentrations remain therapeutic and
drug does not persist after awakening [62].
g-Hydroxybutyrate effects on sleep architecture

GHB is a CNS depressant that has several distinct effects on sleep, the
most notable of which is increase in slow-wave sleep percentages (which
are part of non-REM sleep). Slow-wave sleep, also known as stages 3 and
4 sleep (in the new nomenclature, N3) or delta sleep (named after the
high-amplitude delta waves that characterize this sleep stage) is believed
to exert a restorative component to sleep. Agents that promote slow-wave
sleep percentages, or therapies that can promote increased slow-wave sleep
pressure (such as physical exercise, including aqua aerobics), are now being
investigated and used in the treatment of several chronic painful disorders,
including fibromyalgia. At low doses (less than 30 mg/kg) GHB allows the
normal cycling of non-REM and REM sleep to continue without disruption
[63–66]. REM sleep percentages are not altered by this drug (normally com-
posing 20% of total sleep time in healthy adult humans). GHB may increase
total sleep time also. In concert with the increase of slow-wave sleep percent-
ages seen with GHB use, a tandem increase in growth hormone is also
reported, which is expected because growth hormone release is tightly
coupled to the state of slow-wave sleep [66,67].
Multiple studies confirm GHB treatment substantially improves the signs
and symptoms of narcolepsy [63,67–70]. GHB is administered to patients
who have documented narcolepsy with or without cataplexy. GHB in the
form of sodium oxybate is FDA indicated for the treatment of these disor-
ders and must be prescribed only by a registered prescriber who is recorded
by Jazz Pharmaceuticals (the makers of sodium oxybate) as a certified
prescriber. The drug is dispensed from one central pharmacy in the United
States located in St. Louis and shipped to patients by FedEx.
Adverse effects
GHB carries a moderate abuse potential and recreational abuse of illicit
forms of the drug has been widely documented, particularly in the
504 AHMED
bodybuilding community [71]. Bodybuilders seek out illicit formulations of

GHB because of alleged anabolic properties related to increased growth
hormone release, sometimes ingesting extreme quantities over long periods
of time. Long-term effects of GHB on muscle mass and fat metabolism
are not formally studied but weight gain is documented as an adverse effect
in clinical trials [66]. This finding may be attributable to increased muscle
mass because body mass index has been documented to decrease in
a 6-month period of consistent use of sodium oxybate [72]. Reports of
addiction and withdrawal syndrome after abrupt discontinuation of long-
term street use of GHB formulations have been published but when used
at therapeutic doses for up to 44 months withdrawal syndromes have not
been recorded after sudden cessation [73].
The agent is classified as a schedule III controlled drug by federal law.
Diversion of the drug to an individual for whom it is not prescribed is
a felony and patients and practitioners need to be educated in detail as to
how to manage the drug at home, including keeping it under lock and
key. A specific risk management program has been developed by the man-
ufacturer to ensure safest prescribing and dispensing practices [74].
Common adverse effects experienced at therapeutic doses (noted at least
5% greater than placebo-medicated controls) include daytime somnolence,
nocturnal enuresis, nausea, confusion, and sometimes vomiting [75]. This
drug should never be combined with alcohol. If the patient wishes to imbibe
alcohol for a special occasion, the drug should be discontinued for that
evening. Combined use with alcohol can result in serious respiratory depres-
sion. Sodium oxybate should not be used in combination with sedative
hypnotics or other CNS depressants.
Several patients who had obstructive sleep apnea have been reported as
worsening on this drug but this was not associated with changes in desatu-
ration [76,77] and no dose-related changes in respiratory function are noted.
Almost all trials of this drug, however, have been conducted in the presence
of concomitant stimulant therapy.
Treatment regimens for restless legs syndrome

Restless legs syndrome (RLS) is a common but underdiagnosed sensori-
motor disorder characterized by an uncomfortable sensation in the legs
relieved by movement [78]. Four essential diagnostic criteria for RLS are
shown in Box 1. The hallmark of this disorder is a circadian rhythmicity
in symptoms, such that symptoms emerge in the evening some hours before
sleep onset.
RLS frequently results in significant sleep-onset insomnia and occasion-
ally sleep-maintenance insomnia. RLS is also associated with impaired sleep
quality [79] and is poorly recognized by patients and clinicians alike. RLS
affects 2.5% of the general population, increases in incidence with increasing
age, and affects women more frequently than men [80].
Box 1. Essential diagnostic criteria for diagnosis

of restless legs syndrome
A compulsion to move the legs, usually to relieve (or sometimes
accompanied by) an uncomfortable unpleasant sensation
usually in the legs
Sensations usually exclusively present or worsened during
periods of inactivity, such as recumbency or sitting
Relief of these sensations partially or totally by movement,
including stretching and walking
Sensations maximal or exclusively present during the evening
or night
Data from Ferini-Strambi L. RLS-like symptoms: differential diagnosis by his-

tory and clinical assessment. Sleep Med 2007;8(Suppl 2):S3–6.
The pathophysiology of RLS is unclear but a dysregulation of the circa-

dian rhythm of dopamine is implicated. Medications augmenting dopami-
nergic tone are effective therapies and, in fact, response of symptoms to
these agents is considered supportive diagnostic criteria. Dopaminergic
medications are first-line treatments for RLS [81]. Second-line therapies
include opioids, followed by anticonvulsants; third-line treatments are the
benzodiazepines. These latter treatments are not discussed in this article.
The focus on RLS therapies is on dopaminergic agonists with particular
emphasis on the two non–ergot-derived dopamine agonists pramipexole
and ropinirole, which are the only FDA-approved agents to treat moderate
to severe idiopathic RLS.
Dopaminergic agents in the treatment of restless legs syndrome

Dopaminergic medications are effective and safe in the treatment of RLS.
Two FDA-approved medications are currently licensed for treatment of this
disorder: pramipexole and ropinirole. These non-ergot dopamine D2/D3
agonists are first line and preferred to ergot dopamine receptor agonists
because they cause fewer adverse events. Ergoline dopamine agonists are
associated with valvular heart defects and pulmonary fibrosis [82–84], two
undesirable side effects seen with their use in Parkinson disease. Although
therapeutic doses of these agents for the treatment of RLS are much lower
(by orders of magnitude) it is still preferable to avoid them unless intoler-
ance has been demonstrated with FDA-approved agents that have improved
safety profiles. Even though doses of non-ergot dopamine agonists are much
lower than the doses of dopaminergic medications used to treat Parkinson
disease in which these serious side effects were noted, no long-term data exist
confirming the reduced prevalence of valvular heart disease or pulmonary
506 AHMED
fibrosis with these agents because longitudinal data to date have been insuf-
ficient [85,86].
Pramipexole
Pramipexole has been found to be effective at treating RLS in several
studies evaluating the drug’s efficacy in the treatment of moderate to severe
primary RLS. Severity in these studies was determined using a clinical scale,
The International RLS Study Group Rating Scale (IRLS), which has
a maximum possible score of 40. Scores greater than 15 are designated mod-
erate to severe. Montplaisir and colleagues [87,88] evaluated the drug over
a 6-month study period at doses ranging from 0.125 to 1.0 mg daily, finding
pramipexole effective when comparing the IRLS scores before and after
treatment with drug compared with a placebo-controlled group. These
findings are supported by other more recent studies with more than 1000
subjects in total supporting pramipexole as an effective and safe treatment
[89–95].
Ropinirole
Ropinirole is also established as safe and effective in the treatment of
RLS. Three randomized controlled studies enrolling approximately 900
patients who had at least moderate RLS (scored by the IRLS) determined
ropinirole improves RLS symptom severity and is well tolerated [96–100].
Adverse effects
Common side effects associated with dopaminergic agonists include nau-
sea, headache, daytime somnolence, and change in bowel habit (diarrhea,
constipation). Fatigue is also reported. Patients should be warned that sud-
den sleep attacks can be associated with dopaminergic agonists, although
these episodes have been reported in patients on Parkinson disease doses,
which are much higher. It is nevertheless appropriate to mention this
when initiating therapy [101,102]. Patients should also be warned that any
sudden compulsive behavior, including gambling, hypersexuality, or other
compulsions, could be associated with these therapies [85]. Family members
should be informed of these effects, which are rare but described. In such in-
stances these medications should be stopped immediately and consultation
sought.
Medications that can precipitate or aggravate restless legs syndrome

Critical care clinicians should be aware that several commonly prescribed
medications in the ICU can worsen or expose RLS syndrome. Any patient
experiencing difficulty initiating sleep, more easily apparent in the step-down
ICU patient, perhaps, who is no longer in a sedated coma, should be
carefully questioned for RLS. Causes of secondary RLS including anemia

and renal insufficiency, and ferritin deficiency should be established and
corrected. If RLS seems to be idiopathic (primary) or possibly familial,
treatment plans should be developed. The medications that can exacerbate
RLS are listed in Box 2. If possible these medicines should be avoided, or
use confined to lower doses in the event of suspected RLS symptoms
manifesting in the ICU.
Drugs promoting wakefulness: modafinil

Several sleep disorders result in symptoms of excessive daytime somno-
lence, including obstructive sleep apnea syndrome and narcolepsy. Specifi-
cally, modafinil is indicated for residual hypersomnolence in the patient
who has fully treated obstructive sleep apnea, for management of excessive
daytime somnolence [103] as a component of narcolepsy [104], and also for
the rare instances of idiopathic hypersomnia, a diagnosis of exclusion [105].
Because of a favorable safety profile determined by American and Canadian
studies and supporting data from Europe, this agent has become an Amer-
ican Academy of Sleep Medicine Standard of Care designation for the treat-
ment of excessive hypersomnolence [106]. Clinicians will therefore see this
agent prescribed more often in the future. An additional indication exists
for the treatment of shift-work sleep disorder, which does raise some appro-
priate debate concerning the ethics of treating partial sleep deprivation
(which often accompanies shift-work sleep disorder) with stimulants [103].
With the lack of adequately powered datasets examining the impact of
stimulants on healthy sleep-deprived adults we cannot recommend their
use in this population at this time. Additionally, with the ubiquitous sleep
deprivation in our modern sleep machismo culture [2], patients who have
Box 2. Medication classes that may worsen restless legs

syndrome symptoms
Antipsychotics (eg, haloperidol, perphenazine)
Antiemetics (eg, metoclopramide, prochlorperazine)
Antihistamines (eg, diphenhydramine)
H2 blockers (eg, cimetidine, ranitidine)
Calcium channel blockers (eg, verapamil, nifedipine, diltiazem)
Anticonvulsants (eg, phenytoin)
Antidepressants (eg, amitriptyline, lithium, mirtazapine,
fluoxetine)
Data from Partinen M. Challenging issues: sleep-wake, augmentation and qual-

ity of life. Sleep Med 2007;8(Suppl 2):S19–24.
508 AHMED
treated sleep disorders may continue to be sleepy because of insufficient

sleep syndrome, which may present as refractory daytime somnolence.
Insufficient total sleep time should always be excluded based on careful his-
tory and sleep log data and perhaps more objective testing before resorting
to stimulants of any kind.
Psychostimulants are indicated as adjunctive treatment to improve day-
time performance. Previously psychostimulants were confined to the indirect
sympathomimetics [107], including amphetamines and methylphenidate, but
modafinil, a wake-promoting agent, offers improved safety over these older
agents. The FDA recognized modafinil as a first-line treatment choice for
wake promotion [62]. Focus is therefore restricted to this agent.
Modafinil represents a novel agent in a class of its own and offers the first
alternative to traditional psychostimulants, which carry greater risks of
dependence and abuse. This improved profile is reflected in a schedule IV
classification for modafinil compared with schedule II for older traditional
psychostimulants. Importantly, modafinil is not associated with rebound
hypersomnolence (associated with increase abuse risk) and post-market
surveillance studies have shown that potential for abuse [108] with modafinil
is low [62].
Indirect sympathomimetics act by increasing monoamine concentrations
in the synaptic cleft through augmented release of norepinephrine, seroto-
nin, and dopamine, and enhancing their tone by blocking reuptake activity
[107]. Modafinil enhances wakefulness through several mechanisms, by
inhibiting GABA release in the cerebral cortex through serotonergic means
and exerting an enhanced dopaminergic tone by activating dopaminergic re-
uptake inhibition [62]. Dopamine can be thought of as the neurohormone of
wakefulness. Additionally, modafinil inhibits the norepinephrine reuptake
transporter, which thus diminishes the sleep-promoting propensity of the
ventrolateral preoptic nucleus [109,110]. In contrast to older agents, moda-
finil does not disrupt sleep architecture or subjective sleep complaints in
healthy normal subjects [111] or patients who have narcolepsy [112], a factor
that can be a deterrent to compliance despite debilitating hypersomnolence.
Modafinil’s efficacy has been measured in the reduction in number of
sleep attacks, which are irresistible episodes of involuntary sleepiness, a fea-
ture of narcolepsy. Sleep attacks have been improved by 71% in patients
who have narcolepsy in clinical trial settings [113,114]. Objective measures
of sleep latency, a measure of propensity of sleepiness assessed by a specific
test known as the Multiple Sleep Latency Test, have also been shown to be
improved with modafinil use [115,116]. Modafinil also improves scores on
the Maintenance of Wakefulness Test, which is a measure of wakefulness
propensity [115]. Subjective improvement in daytime somnolence has also
been documented using improvement in scores on the Epworth Sleepiness
Scale as a primary endpoint, although this scale has several deficiencies.
The drug was well tolerated by patients in these clinical trial settings and
overall lacks the cardiovascular complications of other psychostimulants,
including hypertension and arrhythmia [62]. Modafinil reduces the peak

levels of ethinyl estradiol, so women of childbearing age must be informed
of alternate methods of contraception during therapy and up to 1 month
after discontinuing modafinil [62].
Although abuse propensity with this drug is lower than with traditional
agents isolated reports of a psychotropic high have been reported when
used by individuals experienced with drug abuse. Euphoria has been
reported. As with all stimulants, individuals on long-term use, those who
have prior abuse, and those who have comorbid psychiatric diagnoses are
at greater risk for abuse of modafinil.
Modafinil has a half-life of 9 to 14 hours enabling once-daily dosing,
although patients who have narcolepsy have extreme sleep propensity and
usually require the medication twice a day [104]. Modafinil comes in
100-mg tablets. A starting dose of 200 mg is usual with a view to reaching
a total dose of 400 mg per day in two divided doses. This is the maximum
dose according the FDA but anecdotal reports document the use of
600 mg daily for management of narcolepsy and often this is given in a split
dose formulation of 400 mg in the morning and 200 mg in the afternoon
[62]. Some clinicians have used up to 1200 mg daily in patients. Long-
term data on adverse effects with modafinil at the FDA-approved dose or
greater than approved doses are lacking and we would advise avoiding these
latter doses. Patients should be informed that headache is commonly asso-
ciated with modafinil initiation, although this is rarely sufficient to prompt
discontinuation.
A new isomeric form of modafinil is in development and investigation.
Armodafinil is a combination of the R and S isomers of modafinil. These
isomers differ in half-life duration; R is longer acting with a half-life of 10
to 14 hours, whereas S modafinil is more rapidly dissipated with a half-
life of 3 to 4 hours [2,62,103,105–117]. In combination, T max (time taken
to reach maximum serum concentration) is reached rapidly at 2 hours after
ingestion and half-life is 15 hours [117], suggesting a more ideal once-in-the-
morning agent and perhaps a more effective counteracting agent to
afternoon hypersomnolence, but comparative objective data are lacking
presently. Caution must always be exercised in the delayed ingestion of stim-
ulants that could result in sleep-onset insomnia if taken too late in the day.
Summary
Sleep disorders are common and their diagnosis is becoming more wide-
spread with improved awareness among clinicians and patients. The arma-
mentarium for the pharmacologic treatment of sleep disorders is rapidly
widening, demanding that clinicians be aware of their indications, adverse
effects, and interactions. As disorders, such as narcolepsy, shift-work sleep
disorder, and RLS, are more readily identified, pharmacologic treatments
for these conditions will also become more common.
510 AHMED
Specifically, insomnia is increasingly recognized to be a widely prevalent

disorder with enormous patient morbidity and societal consequences. The
management and evaluation of insomnia is finally garnering the recognition
it deserves and current efforts in the investigative literature and pharmaceu-
tical industry are testament to this revitalization. Insomnia pharmacother-
apy is now firmly emerging from its infancy. Newer agents afford specific
treatment options in the management of insomnia in what is increasingly
understood to be a diverse, chronic, and complex disorder, while also yield-
ing insights into the complex mechanisms that control sleep onset. Newer
agents are safer, with more flexible dosing strategies and differing applica-
tions in relation to the timing of the insomnia complaints, whether in sleep
onset or sleep maintenance. These agents offer greater confidence in pre-
scribing and a wider range of possibilities in treatment combinations.
Many clinicians are using several agents in the same patient and there is
an urgent need for combination treatment guidelines, which are likely to
emerge shortly. In the interim, patients are more likely to be medicated
for insomnia and more likely to present on therapy to any practitioner
required to attend the patient. Familiarity with the nature of these agents,
their mechanism of action, and possible adverse effects is warranted even
for the non–sleep practitioner.
References
[1] National Sleep Foundation. 2005 Sleep in America Poll. Available at: http://www.
sleepfoundation.org/site/c.huIXKjM0IxF/b.2419039/k.14E4/2005_Sleep_in_America_Poll.
htm. Accessed May 6, 2008.
[2] Czeisler CA. Sleep deficit: the performance killer. A conversation with Harvard Medical
School Professor Charles A. Czeisler. Harv Bus Rev 2006;84(10):53–9, 148.
[3] Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991
National Sleep Foundation Survey. I. Sleep 1999;22(Suppl 2):S347–53.
[4] Foley D, Ancoli-Israel S, Britz P, et al. Sleep disturbances and chronic disease in older
adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psycho-
som Res 2004;56(5):497–502.
[5] Sanger DJ, Soubrane C, Scatton B. New perspectives for the treatment of disorders of sleep
and arousal. Ann Pharm Fr 2007;65(4):268–74.
[6] Harten P. Fibromyalgia syndrome: new developments in pharmacotherapy). Z Rheumatol
2008;67:75–82 [in German].
[7] NIH State-of-the-Science Conference Statement on manifestations and management of
chronic insomnia in adults. NIH Consens State Sci Statements 2005;22(2):1–30.
[8] NIH State of the Science Conference statement on Manifestations and Management of
Chronic Insomnia in Adults statement. J Clin Sleep Med 2005;1(4):412–21.
[9] Johnson EO, Roehrs T, Roth T, et al. Epidemiology of alcohol and medication as aids to
sleep in early adulthood. Sleep 1998;21(2):178–86.
[10] Johnson JE. Insomnia, alcohol, and over-the-counter drug use in old-old urban women.
J Community Health Nurs 1997;14(3):181–8.
[11] Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev 2003;7(6):523–39.
[12] Neubauer DN. The evolution and development of insomnia pharmacotherapies. J Clin
Sleep Med 2007;3(5 Suppl):S11–5.
[13] Dolan-Sewell RT, Riley WT, Hunt CE. NIH State-of-the-Science Conference on Chronic
Insomnia. J Clin Sleep Med 2005;1(4):335–6.
[14] Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime sedative effects of H1
antihistamines. J Clin Psychopharmacol 2002;22(5):511–5.
[15] Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-
based medicine. Sleep 2004;27(8):1441–2.
[16] Gottesmann C. GABA mechanisms and sleep. Neuroscience 2002;111(2):231–9.
[17] Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol
Exp Ther 2002;300(1):2–8.
[18] National Institutes of Health State of the Science Conference statement on manifestations
and management of chronic insomnia in adults, June 13–15, 2005. Sleep 2005;28(9):1049–57.
[19] Lader M. Dependence on psychotherapeutic drugs. Trans Med Soc Lond 1991;108:53–60.
[20] Petursson H. The benzodiazepine withdrawal syndrome. Addiction 1994;89(11):1455–9.
[21] Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol
Rev 1992;44(2):151–347.
[22] Lader MH. Limitations on the use of benzodiazepines in anxiety and insomnia: are they
justified? Eur Neuropsychopharmacol 1999;9(Suppl 6):S399–405.
[23] Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit 1998;20(5):481–9.
[24] Mendelson WB. Sleepwalking associated with zolpidem. J Clin Psychopharmacol 1994;14:
150.
[25] Tyrer P. Risks of dependence on benzodiazepine drugs: the importance of patient selection.
BMJ 1989;298(6666):102, 104–5.
[26] Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability
and sedative adverse effects. Arch Gen Psychiatry 2006;63(10):1149–57.
[27] Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period, crossover study of ramel-
teon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin
2007;23(5):1005–14.
[28] Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in
older adults with chronic insomnia. Sleep Med 2006;7(4):312–8.
[29] Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor ago-
nist, reduces latency to persistent sleep in a model of transient insomnia related to a novel
sleep environment. Sleep 2005;28(3):303–7.
[30] Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of ra-
melteon in patients with chronic primary insomnia. Sleep Med 2006;7(1):17–24.
[31] Cassone VM. Effects of melatonin on vertebrate circadian systems. Trends Neurosci 1990;
13(11):457–64.
[32] Turek FW, Dugovic C, Zee PC. Current understanding of the circadian clock and the
clinical implications for neurological disorders. Arch Neurol 2001;58(11):1781–7.
[33] Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging therapeutic
targets for sleep disorders. Nat Neurosci 2002;5(Suppl):1071–5.
[34] Brzezinski A. Melatonin in humans. N Engl J Med 1997;336(3):186–95.
[35] Lynch HJ, Wurtman RJ, Moskowitz MA, et al. Daily rhythm in human urinary melatonin.
Science 1975;187(4172):169–71.
[36] Waldhauser F, Dietzel M. Daily and annual rhythms in human melatonin secretion: role in
puberty control. Ann N Y Acad Sci 1985;453:205–14.
[37] Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian mel-
atonin receptor that mediates reproductive and circadian responses. Neuron 1994;13(5):
1177–85.
[38] Reppert SM, Godson C, Mahle CD, et al. Molecular characterization of a second melato-
nin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl
Acad Sci U S A 1995;92(19):8734–8.
[39] Witt-Enderby PS, Dubocovich ML. Molecular pharmacology, regulation and function of
mammalian melatonin receptors. Front Biosci 2003;8:d1093–108.
512 AHMED
[40] Nosjean O, Ferro M, Coge F, et al. Identification of the melatonin-binding site MT3 as the
quinone reductase 2. J Biol Chem 2000;275(40):31311–7.
[41] Dijk DJ, Cajochen C. Melatonin and the circadian regulation of sleep initiation, consolida-
tion, structure, and the sleep EEG. J Biol Rhythms 1997;12(6):627–35.
[42] Krauchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. Neuropsychophar-
macology 2001;25(5 Suppl):S92–6.
[43] Stone BM, Turner C, Mills SL, et al. Hypnotic activity of melatonin. Sleep 2000;23(5):
663–9.
[44] Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of mela-
tonin ingested in the evening. Clin Pharmacol Ther 1995;57(5):552–8.
[45] Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms 1997;
12(6):657–65.
[46] Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375),
a selective MT1/MT2 receptor agonist. Neuropharmacology 2005;48(2):301–10.
[47] Hibberd M, Stevenson SJ. A phase 1 open label study of the absorption, metabolism and
excretion of (14C)-ramelteon (TAK 375) [abstract]. Clin Pharmacol Ther 2004;75:22.
[48] Karim A, Tolbert D, Cao C. Disposition kinetics and tolerance of escalating single doses of
ramelteon, a high affinity MT1 and MT2 melatonin receptor agonist indicated for treat-
ment of insomnia. J Clin Pharmacol 2006;46:140–8.
[49] Stevenson S, Cornelissen K, Clarke E, et al. Study of the absorption, metabolism and
excretion of (14C)-ramelteon (TK 375) [abstract]. Clin Pharmacol Ther 2004;75:22.
[50] Rozerem [package insert], Osaka, Japan: Takeda Pharmaceuticals Inc; 2005.
[51] Mini L, Wang-Weigand S, Zhang J, et al. Reduction in sleep latency during 5 weeks of treat-
ment with ramelteon 8 mg vs placebo in patients with chronic insomnia. Neurology 2006;
66(Suppl 2):A9.
[52] Richardson GS, Wang-Weigand S, Sainati S, et al. Long Term effects of ramelteon on en-
docrine function in patients with chronic insomnia in a double blind placebo controlled
phase III study. Clin Pharmacol Ther 2006;79:P68.
[53] Richardson GS, Wang-Weigand S, Zhang J, et al. Long term safety of ramelteon treatment
in adults with chronic insomnia. Sleep 2006;29(suppl):A233.
[54] Martin Scharf, Hauck M, Stover R, et al. Effect of gamma-hydroxybutyrate on pain, fa-
tigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. Am
J Rheumatol 1998;25:1986–90.
[55] Scharf MB, Baumann M, Berkowitz DV. The effects of sodium oxybate on clinical symp-
toms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003;30(5):1070–4.
[56] Takahara J, Yunoki S, Yakushiji W, et al. Stimulatory effects of GHB on growth hormone
and prolactin release in humans. J Clin Endocrinol Metab 1977;44(5):1014–7.
[57] Teter CJ, Guthrie SK. A comprehensive review of MDMA and GHB: two common club
drugs. Pharmacotherapy 2001;21(12):1486–513.
[58] Food and Drug Administration; gamma hydroxybutyric acid. Press release: Rockville
(MD); November 8, 1990.
[59] Maitre M. The gamma-hydroxybutyrate signaling system in the brain: organization and
functional implications. Prog Neurobiol 1997;51:337–61.
[60] Memalak M, Escriu JM, Stokan O. GHB: an endogenous regulator of energy metabolism.
Neurosci Biobehav Rev 1989;13:197–8.
[61] Mamelak M. Gammahydroxybutyrate: an endogenous regulator of energy metabolism.
Neurosci Biobehav Rev 1989;13(4):187–98.
[62] Thorpy M. Therapeutic advances in narcolepsy. Sleep Med 2007;8(4):427–40.
[63] Mamelak M, Escriu JM, Stokan O. The effects of gamma-hydroxybutyrate on sleep. Biol
Psychiatry 1977;12(2):273–88.
[64] Lapierre O, Montplaisir J, Lamarre M, Bedard MA. The effects of GHB on nocturnal and
diurnal sleep of normal subjects: further consideration of REM-sleep triggering mecha-
nisms. Sleep 1990;13(1):24–30.
[65] Series F, Series I, Courmier Y. Effects of enhancing slow wave sleep by GHB on obstructive
sleep apnea. Am Rev Respir Dis 1992;145:1378–83.
[66] Van Cauter E, Plat L, Scharf MB, et al. Simultaneous stimulation of slow-wave sleep and
growth hormone secretion by gamma-hydroxybutyrate in normal young men. J Clin Invest
1997;100(3):745–53.
[67] Scrima L, Hartman PG, Johnson FH Jr, et al. Efficacy of gamma-hydroxybutyrate versus
placebo in treating narcolepsy-cataplexy: double-blind subjective measures. Biol Psychiatry
1989;26(4):331–43.
[68] Broughton R, Mamelak M. Effects of GHB on sleep/wake patterns in narcolepsy-cata-
plexy. Can J Neurol Sci 1980;7:23–31.
[69] Scharf M, Brown D, Woods M, et al. The effects and effectiveness of GHB in patients with
narcolepsy. J Clin Psychiatry 1985;46:222–5.
[70] Lammers GJ, Arends J, Declerck AC, et al. GHB and narcolepsy: a double blind placebo
controlled study. Sleep 1993;16(3):216–20.
[71] Cooper M. A new danger in drug world is spelled GHB. New York Times. September 29,
1996.
[72] Ristanovic R. Decreased body mass index in narcoleptic patients treated with sodium
oxybate. Sleep 2003;26(Suppl):A87.
[73] US Xyrem Multicenter Study Group. The abrupt cessation of therapeutically administered
sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003;
41(2):131–5.
[74] Fuller DE, Hornfeldt CS, Kelloway JS, et al. The Xyrem risk management program. Drug
Saf 2004;27(5):293–306.
[75] Product Insert Jazz Pharmaceuticals (sodium oxybate) oral solution.
[76] Black JE, Ristanovic R, Mamelak M, et al. Effect of increasing doses of sodium oxybate on
nocturnal saturation: preliminary findings. Sleep 2002;25(Suppl):A474.
[77] Ristanovic R, Black J, Mamelak M, et al. Analysis of dose effects of sodium oxybate on
nocturnal respiratory disturbances. Sleep 2002;25(Suppl):A473.
[78] Ferini-Strambi L. RLS-like symptoms: differential diagnosis by history and clinical assess-
ment. Sleep Med 2007;8(Suppl 2):S3–6.
[79] Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless leg
syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms
and treatment) primary care study. Sleep Med 2004;5(3):237–46.
[80] Rothdach AJ, Trenkwalder C, Haberstock J, et al. Prevalence and risk factors of RLS in an
elderly population: The MEMO study. Memory and Morbidity in Augsburg elderly.
Neurology 2000;54(5):1064–8.
[81] Oertel WH, Trenkwalder C, Zucconi M, et al. State of the art in RLS therapy: practice
recommendations for treating RLS. Mov Disord 2007;22(S18):S466–75.
[82] Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease a new
complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656–62.
[83] Hirani N, Bayliff CC, McCormack DG. Diagnosis and management of pergolide-induced
fibrosis. Mov Disord 2005;20:512–3 [author reply 513].
[84] Dhavan V, Medcalf P, Stegie F, et al. Retrospective evaluation of cardiopulmonary fibrotic
side effects in symptomatic patients from a group of 234 Parkinsons disease patients treated
with cabergoline. J Neural Transm 2005;112:661–8.
[85] Partinen M. Challenging issues: sleep-wake, augmentation and quality of life. Sleep Med
2007;8:S19–24.
[86] Partinen M. Challenging issues: sleep-wake, augmentation and quality of life. Sleep Med
2007;8(Suppl 2):S19–24.
[87] Montplaisir J, Nicolas A, Denesel R, et al. Restless legs syndrome improved by pramipexole
a double blind randomized trial. Neurology 1999;52:938–43.
[88] Montaplasir J, Denesle R, Petit D. Pramipexole in the treatment of RLS: a follow up study.
Eur J Neurol 2000;7:27–31.
514 AHMED
[89] Partinen M, Hirvonen K, Alakuijala A, et al. Pramipexole in restless leg syndrome:

a randomized double blind study. Sleep Med 2006.
[90] Oertel W, Stiasny-Kolster K. Effective treatment of RLS with pramipexole: results of
a 6-week, multicentre, double blind and placebo controlled study [abstract #P2]. Athens
(Greece); 2005.
[91] Winkelman J, Sethi K, Kushida C, et al. Pramipexole is effective and safe in treating RLS
patients: results of 12 weeks placebo controlled, fixed dose study WASM 2005, Berlin
Germany [abstract #058]. Sleep Med 2005;6.
[92] Trenkwalder C, Stiasny-Kolster K, Gr-Psg. Sustained efficacy of pramipexole in restess leg
syndrome. Sleep Med 2005;6:S73.
[93] Montplaisir J. Long term treatment with pramipexole in restless leg syndrome. Eur J Neurol
2006;13:1306–11.
[94] Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless
legs syndrome. Neurology 2006;67(6):1034–9.
[95] Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic
restless legs syndrome: a polysomnographic dose-finding studydthe PRELUDE study.
Sleep Med 2006;7(5):407–17.
[96] Bogan RK, Fry JM, Schmidt MH, et al. Ropinirole in the treatment of patients with RLS:
a US based randomized placebo controlled double blind placebo controlled clinical trial.
Mayo Clin Proc 2006;81:17–27.
[97] Montplaisir J, Karrasch J, Haan J, et al. Ropinirole is effective in the long term
management of restless leg syndrome: a randomized controlled trial. Mov Disord 2006;
21:1627–35.
[98] Georgi I, Ritchie SY, Kirsch JM. Efficacy and tolerability of ropinirole in patients with rest-
less leg syndrome and a baseline IRLS total score O or ¼ to 24 pointsddata from the
ropinirole clinical trial program. Curr Med Res Opin 2006;22:1867–77.
[99] Walters AS, Ondo W, Sethi K, et al. Ropinirole versus placebo in the treatment of restless
leg syndrome (RLS): a 12 week multicenter double blind placebo controlled study
conducted in 6 countries. Sleep 2005;26:A344.
[100] Partinen M, Hirvonen K, Jama L, et al. Open-label study of the long-term efficacy and
safety of pramipexole in patients with restless legs syndrome (extension of the PRE-
LUDE study). Sleep Med 2008, in press.
[101] Bliwise DL, Freeman A, Ingram CD, et al. Randomized double blind placebo controlled
short term trial of ropinirole in restless leg syndrome. Sleep Med 2005;6:141–7.
[102] Adler CH, Hauser RA, Sethi K, et al. Ropinirole for restless leg syndrome: a placebo
controlled cross over trial. Neurology 2004;62:1405–7.
[103] Banerjee D, Vitiello MV, Grunstein RR. Pharmacotherapy for excessive daytime sleepi-
ness. Sleep Med Rev 2004;8(5):339–54.
[104] Proviagil (modafinil) [package insert]. Frazer, PA: Cephalon, Inc; 2006.
[105] Billiard M, Merle C, et al. Idiopathic hypersomnia. Psychiatry Clin Neurosci 1998;52(2):
125–9.
[106] Littner M, Johnson SF, et al. Practice parameters for the treatment of narcolepsy: an
update for 2000. Sleep 2001;24(4):451–66.
[107] Mitler MM, Aldrich MS, et al. Narcolepsy and its treatment with stimulants. ASDA stan-
dards of practice. Sleep 1994;17(4):352–71.
[108] Ferraro L, Antonelli T, et al. Modafinil: an antinarcoleptic drug with a different neuro-
chemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry 1997;
42(12):1181–3.
[109] Wisor JP, Nishino S, et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci
2001;21(5):1787–94.
[110] Wisor JP, Eriksson KS. Dopaminergic-adrenergic interactions in the wake promoting
mechanism of modafinil. Neuroscience 2005;132(4):1027–34.
[111] Saletu B, Frey R, Krupka M, et al. Differential effects of the new central adrenergic agonist
modafinil and d-amphetamine on sleep and early morning behaviour in elderlies. Arznei-
mittelforschung 1989;39(10):1268–73.
[112] Broughton RJ, Fleming JA, George CF, et al. Randomized, double-blind, placebo-
controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in
narcolepsy. Neurology 1997;49(2):444–51.
[113] Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind multicentric study.
Sleep 1994;17(8 Suppl):S107–12.
[114] Boivin DB, Montplaisir J, Petit D, et al. Effects of modafinil on symptomatology of human
narcolepsy. Clin Neuropharmacol 1993;16(1):46–53.
[115] Randomized trial of modafinil as a treatment for the excessive daytime somnolence of
narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000;
54(5):1166–75.
[116] Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy.
US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998;43(1):88–97.
[117] Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single
doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss.
Curr Med Res Opin 2006;22(1):159–67.
Crit Care Clin 24 (2008) 517–531
Sleep and Mechanical Ventilation

Aylin Ozsancak, MD, Carolyn D’Ambrosio, MD,
Erik Garpestad, MD, Greg Schumaker, MD,
Nicholas S. Hill, MD*
Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center,
750 Washington Street #257, Boston, MA 02111, USA
The critical care environment is a harsh one for sleep. Patients with crit-
ical illness have normal or low total sleep time, but sleep architecture is
severely altered. The circadian rhythm is disrupted, with patients spending
as much time sleeping during the day as at night. Consolidation is lost,
stages 1 and sometimes 2 become more prominent, and stages 3 and 4
and rapid eye movement (REM) are severely diminished. Arousals and
awakenings are frequent and contribute to severe fragmentation. Sleep
quantity may be preserved, but quality is lacking. Many factors are thought
to contribute to poor quality sleep in the intensive care unit (ICU). Tradi-
tionally, noise has been considered a major factor in sleep disruption,
although more recent studies suggest that it is responsible for only a minority
of disruptions. Other reasons for disruption of sleep include patient care (eg,
the need to check vital signs or draw blood), effects of medications that can
suppress REM or slow wave sleep, release of cytokines and endocrinologic
effects, and the toxic effects of infection on neurologic function.
Increasingly in recent years, investigators have focused on the role of the
ventilator itself in disrupting sleep, by way of pain and discomfort related to
intubation and suctioning and dyssynchrony between the patient and venti-
lator (Box 1). In the following sections, we briefly review relevant aspects of
normal and abnormal sleep and the control of breathing and discuss evi-
dence that suggests that mechanical ventilation and its modes contribute
to sleep fragmentation. We also consider how long-term mechanical
Dr Hill is funded by Eli Lilly Distinguished Scholarship in Critical Care of the Chest
Foundation and Respironics.
E-mail address: nhill@tufts-nemc.org (N.S. Hill).
518 OZSANCAK et al
Box 1. Contributors to sleep disruption in the intensive care unit

Ventilator mode and other settings (eg, respiratory rate,
tidal volume)
Patient-ventilator dyssynchrony
Discomfort, pain, or anxiety caused by endotracheal tube,
ventilator or acute illness
Air leakage during NIV
Sedation and other medication (eg, analgesics, vasopressors,
corticosteroids)
Patient care activities (eg, vital signs, suctioning, positioning)
Severity of critical illness (eg, sepsis, multiorgan dysfunction)
Noise (eg, conversations, alarms)
Light
ventilation affects sleep in patients with chronic respiratory failure during

invasive and noninvasive ventilation (NIV).
Normal and abnormal sleep

A healthy adult’s sleep architecture normally consists of approximately
80% non-REM and 20% REM stages. Non-REM sleep is further subdi-
vided into three stages (N1, N2, and N3) [1], with stage N1 occurring at
sleep onset for a few minutes. Because it is the transitional stage between
sleep and wakefulness, stage N1 commonly increases when sleep is severely
fragmented, with patients repeatedly awakening and falling back to
sleep. Stage N2, characterized by K-complexes and sleep spindles, also
may increase in the face of fragmentation. Stage N3 is high-voltage
(O 75 mV), ‘‘slow wave’’ (0.5–2 Hz) sleep. More recent nomenclature
has combined what were formerly called stages 3 and 4 into just stage
N3, but for the purposes of this article we use the older nomenclature,
because most of the studies have used the older Rechtschaffen and Kales
terminology [2].
REM sleep is characterized by episodic bursts of rapid eye movements,
low chin muscle tone, irregularities in respiration and heart rate, muscle ato-
nia (except for the diaphragm and ocular muscles), and emergence of
dreams. Non-REM and REM sleep alternate nearly every 90 to 110 minutes
throughout the night such that slow wave sleep and REM sleep occur pre-
dominantly in the first and last third of the night, respectively [3]. REM and
stage N3 are essential for normal restorative sleep, but the latter is
considered the most restorative stage.
Arousals are abrupt shifts of the electroencephalogram frequency that
last 3 or more seconds and are associated with a lightening of sleep by at
SLEEP AND MECHANICAL VENTILATION 519
least one stage. Awakenings refer to abrupt shifts to full wakefulness. Awak-
enings and arousals lead to sleep fragmentation, and their frequent occurrence
diminishes the proportion of REM and slow wave sleep, largely because there
is too little consolidated sleep in the lighter stages to attain them. Severe
fragmentation leads to poor quality sleep, with excessive sleepiness and
cognitive impairment. If sleep deprivation is severe, delirium, immune
suppression, protein catabolism, and respiratory depression can ensue [4].
Control of breathing during normal sleep

During wakefulness, chemoreceptor inputs (from the carotid body for
hypoxia and hypercapnia and from the medullary chemoreceptor for hyper-
capnia) and afferent inputs from chest wall receptors (such as Hering-Breuer
reflex) control ventilation. The behavioral control system (ie, influence of
daily activities such as eating, talking, coughing, or sneezing on ventilation)
and cortical inputs also can override the chemical and mechanical stimuli
[5,6]. During sleep, however, the latter two controllers become quiescent
so that the chemoreceptor and respiratory reflex feedback systems become
the primary controllers of breathing.
At sleep onset, the ‘‘apneic PaCO2 threshold’’ (ie, below which apnea oc-
curs) rises to a level within 1 to 2 mm Hg of the normal awake ‘‘eupnoeic
threshold’’ (ie, the PaCO2 at which apnea is terminated by reinitiation of
breathing) and 2 to 5 mm Hg below sleeping eupnoeic threshold [7]. Partly
as a consequence of these sleep-induced changes in apneic and eupnoeic
thresholds, the transition from wakefulness to sleep causes breathing
instability. Upper airway and respiratory muscle tone diminish, leading to
a decrease in tidal volume. This decrease, combined with a decline in
respiratory drive that slightly lowers respiratory rate, decreases minute ven-
tilation [8] and leads to an increase in PaCO2 by approximately 2 to 3 mm Hg
(and 2–3 mm Hg higher during REM sleep) [9,10], a reduction in PaO2 by 3
to 10 mm Hg, and a reduction in oxygen saturation by 0% to 2% [8,11,12].
Although there is considerable variability within individuals, breathing
often becomes arrhythmic at sleep onset, with the apneic threshold rising
above the waking PCO2 leading to transient apnea in some individuals until
it rises to the sleeping eupnoeic threshold (Fig. 1). This apnea may arouse
the individual and contribute to periodic breathing and lead to hyperventi-
lation and subsequent hypocapnia, which may reinitiate the process as the
individual falls back to sleep. These arousals also may simply cause awak-
enings. As sleep progresses to the latter part of stage 2 and slow wave sleep
(stages 3 and 4), the ‘‘periodic breathing’’ disappears, and breathing
becomes more regular. Consequently, any condition that leads to an
increase in the frequency of transitional stage sleep (eg, a stay in a critical
care unit) also leads to more vulnerability to periodic breathing and central
apneas and subsequently to more arousals, which are the main contributors
to fragmented sleep.
520 OZSANCAK et al
PaCO2
(mmHg)
40
VE (l/min)
30
10
10 20 30 Time (sec)
Awake Sleep Onset NREM Sleep stages
Fig. 1. Schematic changes in apneic and eupnoeic thresholds of PaCO2 (top), and minute venti-
lation (VE) (bottom) during ‘‘sleep onset.’’ The apneic threshold (dashed line) rises with sleep
onset, precipitating apnea until the PaCO2 rises above it, leading to a resumption of breathing
during Non-REM sleep.
Sleep during mechanical ventilation in the acute care setting

Assessment of sleep in the intensive care unit
Monitoring of sleep in the ICU is challenging. Polysomnography (PSG)
is the gold standard for determining the quantity and quality of sleep but is
expensive and time consuming. Sedation, analgesia, acute illness, and elec-
trical interference may alter the electroencephalogram (EEG) tracing,
rendering the interpretation inaccurate. Alternative methods, such as actig-
raphy or the bispectral index, have their own advantages and disadvantages
[13,14]. Actigraphy is a simple, easy method used mainly in outpatients to
measure patient movement as an index of sleep. This approach has severe
limitations in the ICU, however, because motion is hampered in many
patients by restraints and sedation. The bispectral index is derived from
multiple analyses of the raw electroencephalogram, including power and
bispectral, which are further subjected to multivariate analysis. The value
obtained correlates well with the depth of anesthesia in normal volunteers
but has not been validated in the ICU setting [14].
Subjective assessments of sleep have been attempted, including patient
self-assessment based on recall and nurse assessment. Patient assessment
is unreliable because of sedation, delirium/dementia, or recall bias, and
nurse assessment tends to overestimate sleep because of the difficulty in dif-
ferentiating between sedation and actual sleep [15].
Sleep in the intensive care unit

Severe sleep abnormalities in the ICU have been known for decades, hav-
ing been first reported in 1985 among a small series of patients in a surgical
unit who slept less than 2 hours per night during the first 2 nights after
surgery and had virtually no stage 3 or 4 sleep [15]. Subsequent studies have
shown that total sleep times vary enormously among individuals, from 1.7
to 19.4 hours per 24 hours in one study [16]. Sleep in the ICU is often
severely fragmented. Arousals and awakenings have been reported to occur
between 22 and 79 times per hour [17,18], respectively, far in excess of the
normal. The quantity of REM sleep is markedly reduced, ranging from
11% to none [15–17,19–23] compared with the normal of 20% to 25%,
and slow wave sleep is severely reduced. In some patients, atypical sleep
patterns on EEG may reflect medications or the severity of illness, such as
sepsis [20]. The circadian rhythm is also severely disrupted, with noncon-
solidated sleep occurring throughout the 24-hour cycle. Some studies have
recorded a higher percentage of sleep during the waking hours compared
with night [16,18,20,24].
The reasons for the fragmented sleep are undoubtedly multifactorial
(see Box 1). Noise levels in the ICU range from 50 to 80 dBdas loud as
a factorydand noise levels have long been thought to be responsible for
much of the sleep disruption. Several studies have found that although noise
is an important factor, it is responsible for only a minority of the disrup-
tions. Freedman and colleagues [25] found that patients rated human inter-
ventions and diagnostic tests as disruptive as noise. In a study by this group
that monitored noise and EEG tracings in ICU patients for 24 to 48 hours,
only 11.5% of arousals and 17% of awakenings were attributable to noise
[16]. In a similar study, Gabor and colleagues [18] found that 7.1% and
20.9% of arousals and awakenings were attributable to patient care
activities and environmental noise, respectively, accounting for less than
30% of total sleep disruptions. Other factors are responsible for most sleep
disruptions in most patients, and one of these factors may be mechanical
ventilation.
Sleep during invasive mechanical ventilation

Several studies have examined sleep during invasive mechanical ventila-
tion but have been unable to distinguish between disrupted sleep related
to the ventilator per se as opposed to that related to the ICU environment.
In a study based on questionnaires filled out by patients on the day of their
discharge from the ICU, ventilated patients rated themselves as significantly
sleepier than nonventilated patients [25]. No association was established be-
tween a patient’s ventilator status and perceived sleep disruptions by nurse
care activities, noise/light, or sleep quality, however. Although this finding
may suggest that poor sleep quality and disrupted sleep are related to the
ICU environment and not to the ventilator, the limitations of a question-
naire based on patient recall preclude firm conclusions.
Studies that have examined PSG in mechanically ventilated patients
in the ICU have observed the same kinds of sleep fragmentation and alter-
ation of sleep architecture as in patients in the ICU generally: increased
522 OZSANCAK et al
fragmentation, highly variable total sleep time, increased percentage of

stage 1 (and sometimes 2) sleep, and reduced REM and slow wave sleep
[15–24,26,27]. Circadian rhythm is often lost, and the need for sedation,
analgesia, and frequent suctioning contributes to polysomnographic abnor-
malities. A study that monitored PSG for 24 to 48 hours in 22 patients in the
ICU, 20 of whom were receiving mechanical ventilation, found that total
sleep time was normal at an average of 8.8 hours per patient but was com-
prised of a mean of 41 sleep periods that averaged 15 minutes each dispersed
throughout the 24-hour monitoring period (Fig. 2) [16]. There were no sig-
nificant correlations among age, gender, APACHE III score, or length of
ICU stay and the day-versus-night distribution of sleep or arousal index.
Whether this severe sleep fragmentation has adverse effects on weaning or
subsequent outcomes is unknown.
Effect of ventilator mode

Several more recent studies have examined the possibility that the venti-
lator mode itself might contribute to sleep arousals during mechanical
ventilation [17,21–23]. Parthasarathy and Tobin [17] hypothesized that pres-
sure support ventilation would cause more central apneas than assist control
ventilation because it has no backup rate and might hyperventilate patients
(and lower PaCO2 below the apneic threshold) during sleep. Setting assist
control and pressure support adjusted to deliver 8 mL/kg during wakeful-
ness, patients received at least 2 hours each of assist control, pressure
Fig. 2. Disrupted and dispersion of sleep over a 24-hour monitoring period in five subjects in an
ICU. Black areas represent episodes of sleep; white areas represent wakefulness. (From Freedman
NS, Gazendam J, Levan L, et al. Abnormal sleep/wake cycles and the effect of environmental
noise on sleep disruption in the intensive care unit. Am J Respir Crit Care Med 2001;163:
453; with permission.)
support, and pressure support with added dead space in random order dur-
ing a single night. The authors confirmed their hypothesis, observing more
central apneas and worse sleep fragmentation (79 versus 54 arousals and
awakenings per hour [P ! .05]) with pressure support than with assist
control. They also found that the added dead space (which raised PaCO2)
eliminated most of the central apneas and sleep disruption in the pressure
support group (Fig. 3), which was consistent with the hypothesis that over-
ventilation leading to hypocapnea during sleep was responsible for the
worse sleep fragmentation. Six of the 11 patients in the study had congestive
heart failure, however, which may have predisposed them to the develop-
ment of central apneas.
One speculation that derives from the study by Parthasarathy and Tobin
[17] is that lower dose pressure support would eliminate the central apneas
and improve sleep quality. Toublanc and colleagues [22] used a pressure
support of only 6 cm H2Odjust enough to overcome the added breathing
work attributable to the endotracheal tube. In a single night crossover trial,
Fig. 3. Upper panel shows that 6 of 11 mechanically ventilated patients developed apneas dur-
ing pressure support (PS; closed circles) as compared with none during assist control ventilation
(AC; open triangles). Lower panel shows that the addition of dead space virtually eliminated the
apneas during pressure support (open circles). Individual and group mean values are shown.
(From Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill
patients. Am J Respir Crit Care Med 2002;166:1425; with permission.)
524 OZSANCAK et al
they compared low-dose pressure support to assist control set at 10 mL/kg

or enough to suppress spontaneous breathing. They found that although
central apneas were not a problem with low-dose pressure support, assist
control was still preferable; it was associated with better sleep quality, in-
cluding greater proportions of stages 1 and 2 sleep early on and more stages
3 and 4 sleep during the latter part of the night. The authors concluded that
to optimize sleep quality, patients should be ‘‘rested’’ with assist control ven-
tilation at night while undergoing daytime weaning trials. They did not test
an intermediate level of pressure support, however, which might have
avoided overventilation and still unloaded the breathing muscles.
Bosma and colleagues [21] hypothesized that a mode that has the poten-
tial to enhance patient-ventilator synchrony, proportional assist ventilation
(PAV), would also improve sleep quality compared with pressure support.
PAV targets instantaneous inspiratory flow and can respond to increased
patient effort by increasing delivered pressure and flow, depending on the
specific flow and volume assist settings and proportional assist selected
[28,29]. Esophageal and gastric balloons were inserted so that ventilator set-
tings could be adjusted to achieve equivalent reductions in breathing work
with both modes. Thirteen patients were crossed over in random order to
receive PAV or pressure support on consecutive days. Patients had fewer
incidences of auto-triggering, failed triggering, double-triggering, or delayed
cycling with PAV, which was also associated with fewer arousals (Fig. 4)
and consequently more slow wave and REM sleep. The authors concluded
that by optimizing patient-ventilator synchrony compared with pressure
support, PAV improved quality of sleep.
More recently, Alexopoulou and colleagues [23] compared PAVþ to
pressure support in patients manifesting good patient-ventilator synchrony.
PAVþ is an upgraded PAV mode that automatically adjusts inspiratory and
Fig. 4. Linear regression analysis correlates the number of patient-ventilator asynchronies per
hour with the number of arousals per hour. By optimizing patient-ventilator synchrony, PAV
(filled circles) was associated with less asynchrony and fewer arousals than pressure support
(open circles). (From Bosma K, Ferreyra G, Ambrogio C, et al. Patient-ventilator interaction
and sleep in mechanically ventilated patients: pressure support versus proportional assist
ventilation. Crit Care Med 2007;35:1053; with permission.)
expiratory assist settings by calculating resistance and elastance using

300-msec pause maneuvers after random breaths, obviating the need
for insertion of esophageal and gastric balloons, but the authors aimed to
ascertain whether the brief pause maneuvers disrupted sleep. They found
that although PAVþ was associated with enhanced sleep efficiency com-
pared with pressure support in sedated patients, there were no other differ-
ences in sleep quality for sedated and nonsedated patients. The authors also
found that at high levels of assist, both modes induced periodic breathing.
Although this study did not replicate the advantages of PAV over pressure
support observed by Bosma and colleagues [21], the exclusion of patients
who manifestes dyssynchrony on pressure support might have eliminated
the chance of making such an observation.
In summary, these studies demonstrate that the ventilator mode and spe-
cific ventilator settings can contribute to irregular breathing patterns and
sleep fragmentation. In spontaneous breathing modes such as pressure
support or PAV, excessively high settings can predispose to central apneas
by means of overventilation and suppression of the drive to breathe as the
apneic threshold rises with sleep onset. To avoid this problem and poten-
tially improve sleep in the ICU (Box 2), ventilator modes can be set to avoid
overventilation, or the assist-control mode can be used during sleep so that
the backup rate eliminates the central apneas.
Sleep during noninvasive ventilation

NIV, which is the provision of mechanical ventilation without requiring
an artificial airway, usually via a full face or nasal mask, has been used
increasingly in critical care units internationally to treat respiratory failure
mainly caused by chronic obstructive pulmonary disease exacerbations or
congestive heart failure [30,31]. As such, most applications of NIV last
between hours and a few days [32], so most patients wean off before sleep
deprivation is likely to become severe. Many patients with respiratory fail-
ure are at risk for sleep deprivation when they are admitted to a hospital,
however, and even a few more days of poor sleep could be deleterious, so
sleep during acute applications of NIV is of interest. As of yet, no studies
have been published describing sleep during NIV, although the expectation
is that its administration in the critical care environment would be
Box 2. Strategies to optimize sleep quality

during mechanical ventilation
Rest with assist control mode overnight
Avoid overventilation with spontaneous breathing modes
(pressure support or PAV)
Use modes that optimize synchrony (PAV)
526 OZSANCAK et al
associated with the same severe sleep fragmentation observed in other crit-
ically ill patients. Our preliminary investigation of four patients using NIV
in ICUs monitored with PSG for 24 hours supports this expectation; pa-
tients had a marked increase in the frequency of arousals and a paucity of
slow wave or REM sleep (representative hypnogram in Fig. 5). One patient
with pneumonia, whose sleep was disrupted by frequent arousals related to
cough, had no REM or slow wave sleep whatsoever and required intubation
approximately 6 hours after completion of the PSG. The question of
whether severe sleep disruption predicts NIV failure cannot be answered
from our data but may be a topic for a later investigation.
Sleep during mechanical ventilation in the long-term setting

Sleep during long-term invasive mechanical ventilation
In recent years, patients who fail to wean from invasive mechanical ven-
tilation within a couple of weeks have been undergoing earlier tracheostomy
than in the past [33–35]. If sufficiently stable, these patients are then trans-
ferred to postacute care or long-term acute care hospitals, where they con-
tinue on mechanical ventilation and undergo more gradual weaning as their
medical condition stabilizes and they gain strength in response to physical
therapy [36]. A substantial portion of these patients (up to 50%) dies while
in long-term acute care [37]. Most of the survivors (70%) wean and undergo
decannulation. Some patients who fail to wean are able to return home if
Fig. 5. Fragmented sleep pattern of a patient using NIV in the ICU (using oxygen with nasal
cannula for the first 5 hours). Upper panel shows sleep stages (label to left), middle panel
indicates arousals with vertical marks, and black horizontal bars show that bilevel pressures
were 12 cm H2O inspiratory and 5 cm H2O continuously after the first 5 hours, except for a brief
interruption after 9AM. Sleep consisted of mainly stage 1 and 2 with a brief period of stage 3.
The total number of arousals and awakenings was 23/hour. (Aylin Ozsancak and colleagues,
Unpublished data.)
they have the capability and requisite resources. Others remain hospitalized
in long-term acute care or are transferred to a skilled nursing facility.
Little is known about sleep of long-term mechanically ventilated patients
in a long-term acute care setting or at home. It is reasonable to expect that
as the acute illness subsides, fewer interruptions for tests or vital signs are
necessary, and the environment becomes less noisy, sleep quality would
improve. It is expected that sleep fragmentation would diminish, slow
wave and REM sleep would return, and circadian rhythm would be re-
stored, but this has not been established. It also would be expected that sleep
quality at home would approach normal in long-term ventilator users, who
might be supported for up to several decades, depending on their age at
initiation and cause of respiratory failure.
Sleep during long-term noninvasive ventilation

Various different approaches to NIV have been used in the past [38].
During the polio epidemics, so-called ‘‘body’’ ventilators, including negative
pressure ventilators such as iron lungs, provided mechanical ventilatory
assistance long-term to thousands of afflicted individuals. These machines
are rarely used any longer, however, partly because of their lack of portabil-
ity but also because studies during the early 1990s demonstrated that they
exacerbated or even induced obstructive sleep apnea because the negative
pressure was not triggered by the patient, which predisposed the patient
to upper airway collapse caused by asynchrony between upper airway stiff-
ening and ventilator action [39].
Beginning during the mid-1980s, noninvasive positive pressure ventila-
tion (NPPV) was reported as an effective way to stabilize chronic respira-
tory failure caused by neuromuscular disease or chest wall deformity
[40,41]. In these studies, NPPV was applied just nocturnally using the
nasal route. Used in this way, the greater convenience and portability of
NPPV compared with body ventilators and its ability to avoid upper air-
way obstruction led to a rapid switch, so that by the early 1990s, NPPV
was seen as the ventilatory mode of first choice for patients with chronic
respiratory failuredpreferred even to tracheostomy ventilation. Initial
studies on sleep in these patients using withdrawal for periods of time
averaging a week demonstrated that compared with nights when patients
did not use it, nasal NPPV mitigated sleep-related hypoventilation, which
improved nocturnal oxygenation and prevented deterioration in daytime
gas exchange [42]. PSG demonstrated fewer arousals (65 versus 114)
when patients used NPPV, although the percentage of REM sleep was
unaffected [43].
Subsequent PSG in a small cohort of long-term users of NPPV with
restrictive thoracic disease demonstrated the frequent occurrence of oral
air leaks during nasal NPPV, which occurred during most sleep [44] and
for all breaths during slow wave sleep. In some patients, these air leaks
528 OZSANCAK et al
were associated with frequent arousals and diminished the quality of sleep.
In a later study, Teschler and colleagues [45] eliminated the mouth leaks by
taping the mouths of patients using nasal NPPV and demonstrated a reduc-
tion in the frequency of arousals.
NPPV for chronic respiratory failure caused by restrictive thoracic disor-
ders greatly improves nocturnal gas exchange, which is associated with
a marked reduction in the frequency of arousals compared with no ventila-
tory assistance at all. Because of the innate leakiness of the NIV system,
however, mouth leaks can contribute to more arousals than would be the
case if leaks could be eliminated. Some patients seem to accommodate to
the leaks and have relatively few arousals related to them, and others may
respond to strategies aimed at reducing them. Taping of the mouth is prob-
ably not practical in the long-term, but switching to an oronasal mask may
be helpful in some patients.
Effect of ventilator settings on sleep during long-term noninvasive

positive pressure ventilation
Fanfulla and colleagues [46] examined the effect of two different ways
of setting pressure support on sleep quality in nine patients with neuro-
muscular disease who had been established on long-term NPPV. Pressure
support was set in the ‘‘usual’’ manner, which was the maximal tolerated
inspiratory pressure that reduced the awake PaCO2 by more than 5% com-
bined with an extrinsic positive end-expiratory pressure level that ‘‘was
progressively increased in each patient, according to his or her tolerance.’’
‘‘Physiologic’’ pressure support was set using esophageal and gastric ma-
nometry by seeking an inspiratory pressure that reduced the transdiaph-
ragmatic pressure swing by more than 40% but less than 80% and to
avoid any positive deflection in esophageal pressure at the onset of expi-
ration. Extrinsic positive end-expiratory pressure was set at 80% of the
intrinsic positive end-expiratory pressure measured during spontaneous
breathing. The authors found that sleep efficiency (80.6% versus
71.7%), arousal index (16 versus 29.9 events/h), percentage of REM
(17.3% versus 9.1%), and ineffective trigger efforts were improved by
physiologic as opposed to usual pressure support (all P ! .05). These
findings demonstrated that the settings for pressure support influence
sleep quality, but they do not establish that manometry is necessary to
achieve optimal settings. No single ‘‘usual’’ way to set pressure support
has been agreed upon for patients with chronic respiratory failure caused
by neuromuscular disease. The ‘‘usual’’ approach used by Fanfulla and
colleagues [46] was aggressive and arrived at inspiratory and expiratory
pressures in some patients that were considerably higher than those
determined physiologically. Other authorities prefer determination of
pressures in a sleep laboratory, with pressures selected to minimize
respiratory events [47], and still others favor a gentler approach that
gradually increases inspiratory pressure as tolerated over a period of

weeks, targeting a reduction in symptoms and daytime PaCO2 [48]. These
approaches were not tested in the study by Fanfulla and colleagues,
however.
Summary
Mechanical ventilation is associated with altered sleep, both in critical
care and long-term settings. In ICUs, severe disruption of sleep is the rule,
with patients typically encountering severe fragmentation, increasing
proportions of transitional stages of sleep (stage 1 in particular), and
loss of slow wave and REM sleep. Circadian rhythms are disrupted,
with multiple short periods of sleep distributed throughout the day/night
cycle. Mechanical ventilation is associated with these same sleep abnor-
malities, but it is difficult to separate the effects of ventilation from those
of critical illness, the ICU environment with its noisiness and frequent dis-
turbances, medications, and discomfort related to interventions and the
disease itself. Recent studies show that the ventilator mode and inappro-
priate settings can contribute to sleep fragmentation, however, and it is
important to avoid overventilation when using spontaneous breathing
modes. NIV in the acute setting seems to be associated with the same
sleep abnormalities as invasive ventilation. Long-term NPPV is well estab-
lished to assist ventilation nocturnally for patients with chronic respira-
tory failure caused by restrictive thoracic disorders. In this setting, it
improves gas exchange and sleep quality, but in some susceptible individ-
uals, the nearly ubiquitous mouth leaks can contribute to an increase in
arousals.
References
[1] Iber C, Ancoli-Israel S, Chesson AL, et al; the American Academy of Sleep Medicine. The
AASM manual for the scoring of sleep and associated events: Rules, terminology and tech-
nical specifications. 1st edition. Westchester, Illinois: American Academy of Sleep Medicine,
2007.
[2] Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scor-
ing system for sleep stages of human subjects. In: Service PH, editor. Washington, DC:
US Government Printing Office; 1977.
[3] Carskadon MA, Dement WC. Normal human sleep: an overview. In: Kryger MH, Roth T,
Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia:
Elsevier Saunders; 2005. p. 13–23.
[4] Weinhouse G, Schwab R. Sleep in the critically ill patient. Sleep 2006;29:1292–301.
[5] Eckert DJ, Jordan AS, Merchia P, et al. Central sleep apnea: pathophysiology and treat-
ment. Chest 2007;131:595–607.
[6] White D. Central sleep apnea. In: Kryger MH, Roth T, Dement WC, editors. Principles
and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005.
p. 969–82.
530 OZSANCAK et al
[7] Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO2 below
eupnoe as a determinant of ventilatory stability in sleep. J Physiol 2004;560:1–11.
[8] Wornsnop C, Kay A, Pierce R, et al. Activity of respiratory pump and upper airway muscles
during sleep onset. J Appl Physiol 1998;85:908–20.
[9] Berthon-Jones M, Sullivan CE. Ventilatory and arousal responses to hypoxia in sleeping
humans. Am Rev Respir Dis 1982;125:632–9.
[10] Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults.
Am Rev Respir Dis 1982;126:758–62.
[11] Giglio P, Lane JT, Barkoukis TJ, et al. Sleep physiology. In: Barkoukis TJ, Avidan AY,
editors. Review of sleep medicine. 2nd edition. Philadelphia: Elsevier; 2007. p. 29–41.
[12] Rist KE, Daubenspeck JA, McGovern JF. Effects of non-REM sleep upon respiratory drive
and the respiratory pump in humans. Respir Physiol 1986;63:241–56.
[13] Bourne RS, Minelli C, Mills GH, et al. Clinical review: sleep measurement in critical care
patients: research and clinical implications. Crit Care 2007;11:226–43.
[14] Watson P. Measuring sleep in critically ill patients: beware the pitfalls. Crit Care 2007;11:
159–60.
recording of sleep in nine patients receiving postoperative care. BMJ 1985;290:1029–32.
Med 2001;163:451–7.
[17] Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill patients.
[18] Gabor JY, Cooper AB, Crombach SA, et al. Contribution of the intensive care unit envi-
ronment to sleep disruption in mechanically ventilated patients and healthy subjects.
[19] Gottschlich MM, Jenkins ME, Mayes T, et al. The 1994 Clinical Research Award: a prospec-
tive clinical study of the polysomnographic stages of sleep after burn injury. J Burn Care
Rehabil 1994;15:486–92.
[21] Bosma K, Ferreyra G, Ambrogio C, et al. Patient-ventilator interaction and sleep in mechan-
ically ventilated patients: pressure support versus proportional assist ventilation. Crit Care
Med 2007;35:1048–54.
[22] Toublanc B, Rose D, Glerant JC, et al. Assist-control ventilation vs. low levels of pressure
support ventilation on sleep quality in intubated ICU patients. Intensive Care Med 2007;
33:1148–54.
[23] Alexopoulou C, Kondili E, Vakouti E, et al. Sleep during proportional-assist ventilation
with load-adjustable gain factors in critically ill patients. Intensive Care Med 2007;33:
1139–47.
[24] Hardin KA, Seyal M, Stewart T, et al. Sleep in critically ill chemically paralyzed patients
requiring mechanical ventilation. Chest 2006;129:1468–77.
[26] Edwards GB, Schuring LM. Pilot study: validating staff nurses observations of sleep and
wake states among critically ill patients, using polysomnography. Am J Crit Care 1993;2:
125–31.
[27] Valente M, Placidi F, Oliveira AJ, et al. Sleep organization pattern as a prognostic marker at
the subacute stage of post-traumatic coma. Clin Neurophysiol 2002;113:1798–805.
[28] Younes M, Puddy A, Roberts D, et al. Results of an initial clinical trial. Am Rev Respir Dis
1992;145:121–9.
[29] Younes M. Proportional assist ventilation: a new approach to ventilatory support. Theory.
[30] Maheshwari V, Paioli D, Rothaar R, et al. Utilization of noninvasive ventilation in acute

care hospitals: a regional survey. Chest 2006;129:1226–33.
[31] Demoule A, Girou E, Richard JC, et al. Increased use of noninvasive ventilation in French
intensive care units. Intensive Care Med 2006;32:1756–65.
[32] Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospective trial of noninvasive positive
pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 1995;151:
1799–806.
[33] Armstrong PA, McCarthy MC, Peoples JB. Reduced use of resources by early tracheostomy
in ventilator-dependent patients with blunt trauma. Surgery 1998;124:763–6.
[34] Brook AD, Sherman G, Malen J, et al. Early versus late tracheostomy in patients who
require prolonged mechanical ventilation. Am J Crit Care 2000;9:352–9.
[35] Rodriguez JL, Steinberg SM, Luchetti FA, et al. Early tracheostomy for primary airway
management in the surgical critical care setting. Surgery 1990;108:655–9.
[36] Hansra IK, White AC, Hill NS. Management in long term acute care hospitals. In:
Ambrosino N, Goldstein R, editors. Long-term mechanical ventilation. New York: Marcel
Dekker, in press.
[37] Carson SS, Bach PB, Brzozowski L, et al. Outcomes after long-term acute care: an analysis of
133 mechanically ventilated patients. Am J Respir Crit Care Med 1999;159:1568–73.
[38] Mehta S, Hill NS. Noninvasive ventilation. Am J Respir Crit Care Med 2001;163:540–77.
[39] Levy RD, Cosio MG, Gibbons L, et al. Induction of sleep apnoea with negative pressure
ventilation in patients with chronic obstructive lung disease. Thorax 1992;47:612–5.
[40] Bach JR, Alba AS. Management of chronic alveolar hypoventilation by nasal ventilation.
Chest 1990;97:52–72.
[41] Kerby GR, Mayer LS, Pingleton SK. Nocturnal positive pressure ventilation via nasal mask.
[42] Hill NS, Eveloff SE, Carlisle CC, et al. Efficacy of nocturnal nasal ventilation in patients with
restrictive thoracic disease. Am Rev Respir Dis 1992;145:365–71.
[43] Masa Jimenez JF, Sanchez de Cos Escuin J, Vicente CD, et al. Nasal intermittent positive
pressure ventilation: analysis of its withdrawal. Chest 1995;107:383–8.
[44] Meyer TJ, Pressman MR, Benditt J, et al. Air leaking through the mouth during nocturnal
nasal ventilation: effect on sleep quality. Sleep 1997;20:561–9.
[45] Teschler H, Stampa J, Ragette R, et al. Effect of mouth leak on effectiveness of nasal bilevel
ventilatory assistance and sleep architecture. Eur Respir J 1999;14:1251–7.
[46] Fanfulla F, Delmastro M, Berardinelli A, et al. Effects of different ventilator settings on sleep
and inspiratory effort in patients with neuromuscular disease. Am J Respir Crit Care Med
2005;172:619–24.
[47] Benhaw SW. Sleep study: home or office? Pro. Chron Respir Dis 2007;4:117–8.
[48] Garpestad E, D’Ambrosio C, Hill NS. Sleep study: home or office? Con. Chron Respir Dis
2007;4:119–20.
Crit Care Clin 24 (2008) 533–549
Diagnosis and Management of Obesity

Hypoventilation Syndrome in the ICU
Won Y. Lee, MDa, Babak Mokhlesi, MD, MScb,*
a
Section of Pulmonary and Critical Care Medicine, The University of Chicago Pritzker
School of Medicine, 5841 South Maryland Avenue, Sleep Disorders Center W 4,
Chicago, IL 60637, USA
b
Section of Pulmonary and Critical Care Medicine, The University of Chicago Pritzker School
of Medicine, 5841 South Maryland Avenue, MC 0999/Room L11B, Chicago, IL 60637, USA
Historical perspective and definition

In 1955, Auchincloss and colleagues [1] described in detail the first case of
a patient who had obesity hypoventilation syndrome (OHS). The following
year, Burwell and colleagues [2] compared patients who had OHS to an
obese, somnolent Charles Dickens’ character and popularized the descrip-
tion ‘‘Pickwickian syndrome.’’ The central features of OHS include obesity
(body mass index [BMI] R 30 kg/m2), chronic alveolar hypoventilation
leading to daytime hypercapnia (PaCO2 R 45 mm Hg), and sleep-disordered
breathing [3,4]. Essential to the diagnosis is exclusion of other causes of
alveolar hypoventilation, such as severe obstructive or restrictive pulmonary
disease, severe hypothyroidism, neuromuscular diseases, or other central
hypoventilation syndromes (Box 1).
Although obesity hypoventilation syndrome can exist autonomously, it is
frequently associated with obstructive sleep apnea (OSA), which is charac-
terized by recurrent upper airway obstruction resulting in apneas, hypo-
pneas, oxygen desaturation, and arousals from sleep. Approximately 90%
of patients who have OHS exhibit sleep-disordered breathing consisting of
obstructive apneas and hypopneas (apnea-hypopnea index [AHI] R 5),
whereas the remaining 10% of patients who have OHS have an AHI less
than 5 [4–6]. Because of this frequent association the term ‘‘hypercapnic
OSA’’ has been interchangeably used with OHS. In fact, most patients
who have OHS suffer from severe OSA (AHI R 30) [4].
E-mail address: bmokhles@medicine.bsd.uchicago.edu (B. Mokhlesi).
534 LEE & MOKHLESI
Box 1. Common causes of hypercapnia other than obesity

hypoventilation syndrome
Chest wall restrictive disorders (eg, scoliosis)
Severe interstitial lung disease
Severe obstructive lung disease (FEV1 < 1 L or <35% predicted)
CNS structural defectsdtumor, cerebrovascular accidents,
brainstem or spinal cord lesions
Neuromuscular disorders
Severe hypothyroidism/myxedema
Severe electrolyte abnormalities (eg, hypophosphatemia and
hypocalcemia)
Idiopathic central alveolar hypoventilation
Metabolic alkalosis caused by high doses of loop diuretics
Morbidity and mortality

OHS is often unrecognized and treatment is frequently delayed, and can
cause secondary erythrocytosis, pulmonary hypertension, and cor pulmo-
nale. The delay in recognizing and treating this condition increases health
care resource use and the likelihood of requiring hospitalization compared
with patients who have similar degrees of obesity [7]. The most common rea-
sons for hospitalizations are dyspnea and acute-on-chronic hypercapnic re-
spiratory failure. Once hospitalized, patients who have OHS are more likely
to require intensive care monitoring and invasive mechanical ventilation.
When compared to eucapnic morbidly obese hospitalized patients, OHS pa-
tients require more ICU admissions (40% versus 26%) and a large percent-
age also require long-term care on discharge (19% versus 2%) [8]. Although
many of these patients have had prior hospitalizations because of acute-
on-chronic respiratory failure, the formal diagnosis of OHS is usually estab-
lished late, in the fifth or sixth decade of life, and after consultation by a
pulmonary and critical care specialist (Box 2) [5,8,9].
Compared to patients who have similar degrees of obesity, patients who
have OHS have a higher mortality. Earlier case series of hospitalized pa-
tients who had severe OHS reported a mortality rate approaching 50%, in-
cluding cases of sudden unexpected deaths [10,11]. The reason for the
increased risk for mortality in these older series was attributed to progres-
sive hypercapnia and obtundation or massive pulmonary embolism. In
two recent prospective studies, however, there were no in-hospital deaths
among a total of 64 consecutive patients who had OHS [8,12]. A retrospec-
tive study reported that 7 out of 15 patients who had OHS (46%) who re-
fused long-term noninvasive positive airway pressure therapy died during
an average of 50-month follow-up period. In contrast, out of the 54 patients
who accepted and were adherent to long-term treatment with positive
MANAGEMENT OF OBESITY HYPOVENTILATION SYNDROME 535
Box 2. Adverse events associated with undiagnosed

and untreated obesity hypoventilation syndrome
Increased health care costs
Increased need for ICU monitoring
Higher requirement for invasive mechanical ventilation during
hospitalization
Increased need for long-term care on discharge
Worse quality of life
Higher risk for pulmonary hypertension
Increased risk for death
airway pressure therapy, only 3 (6%) died [6]. Similarly, a prospective study
of 47 OHS patients (of which only 13% received long-term treatment of hy-
poventilation) were followed after hospital discharge for 18 months. The
mortality of patients who had OHS was 23% versus 9% in patients who
had a similar degree of obesity but did not have hypoventilation (adjusted
hazards ratio 4.0) and most deaths occurred in the first 3 months after hos-
pital discharge [8]. Other long-term studies have reported mortality rates of
less than 10% during a 2-year follow-up in patients who have OHS who are
adherent to noninvasive positive pressure ventilation (NPPV) [7,13,14].
Surprisingly, the degree of daytime hypoxia before the initiation of NPPV
therapy seems to be a better predictor of long-term mortality than the degree
of hypercapnia [14].
Pathophysiology
The mechanism by which morbid obesity leads to hypoventilation is com-
plex and not fully understood. Proposed mechanisms include abnormal re-
spiratory system mechanics because of obesity, impaired central responses
to hypercapnia and hypoxia, sleep-disordered breathing, and neurohor-
monal abnormalities, such as leptin resistance (Box 3) [4,15].
Obesity imposes a significant mechanical load leading to a reduction in to-
tal respiratory system compliance, increased lung resistance, and a relative
state of respiratory muscle weakness all leading to increased work of breath-
ing [16–19]. However, obesity does not appear to be the only determinant of
hypoventilation because less than a third of morbidly obese patients develop
chronic hypercapnia [20,21]. Other determinants of hypoventilation include
a blunted central responsiveness to hypercapnia and hypoxia, a state of leptin
resistance (a satiety protein that increases ventilation), and sleep-disordered
breathing. The role of sleep-disordered breathing in the pathogenesis of hypo-
ventilation has been well established by the resolution of hypercapnia in most
patients who have OHS with either positive airway pressure therapy or tra-
cheostomy without any concomitant change in body mass [6,22–28].
536 LEE & MOKHLESI
Box 3. Mechanisms implicated in obesity hypoventilation

syndrome
Decreased chest wall and lung compliance secondary to excess
adipose tissue
Increased upper airway and total respiratory system resistance
Respiratory muscle weakness
Impaired central driveddecreased ventilatory response to
hypercapnia and hypoxia
Increased work of breathing
Coexistent obstructive sleep apnea
Neurohormonal abnormalitiesdleptin resistance
Epidemiology
Because of the global obesity epidemic and the high prevalence of OSA in
the general population, critical care physicians are likely to encounter pa-
tients who have acute-on-chronic respiratory failure attributable to OHS
in their clinical practice. The prevalence of OHS amongst patients who
have OSA has been estimated between 10% and 20% and is higher in the
subgroup of patients who have extreme obesity (Fig. 1) [20,21]. The preva-
lence of OHS is even higher (31%) in obese patients admitted to inpatient
general medicine services [8].
Clinical presentation
OHS is slightly more prevalent in men and most patients are diagnosed in
their fifth or sixth decade of life. The vast majority of patients have the clas-
sic symptoms of OSA, including loud snoring, nocturnal choking episodes
with witnessed apneas, excessive daytime sleepiness, and morning head-
aches. In contrast to eucapnic OSA, patients who have stable OHS fre-
quently complain of dyspnea and may have signs of cor pulmonale. With
acute-on-chronic hypercapnic respiratory failure, patients who have OHS
can develop worsening dyspnea and obtundation in severe cases.
When evaluating a patient with hypercapnia, a thorough investigation
should be performed. A complete neurologic examination can diagnose
neuromuscular diseases, primary central nervous system structural defects,
or spinal cord injury. Medication and substance use should be carefully re-
viewed, searching for sedative, narcotic, or ethanol use that may lead to cen-
tral nervous system depression, and a toxicology screen should be
considered. Other conditions that are frequently associated with hypercap-
nia should also be excluded (see Box 1).
Physical examination findings can include a plethoric obese patient who
has an enlarged neck circumference, crowded oropharynx, and a prominent
40
Percent of patients with OHS

30
20
10
0
30-34 35-39 >40
Body Mass Index Categories (kg/m2)
Fig. 1. Prevalence of OHS in patients who have OSA by categories of BMI in two studies per-
formed in France [20] and the United States [21]. Squares, United States (n ¼ 359, mean BMI
43 kg/m2); circles, France (n ¼ 1141, mean BMI 34 kg/m2). The higher prevalence of extreme
obesity in the United States is associated with a higher prevalence of OHS. Sleep Breath
2007;11:122; with permission.)
pulmonic valve closure (loud P2) on cardiac auscultation. The patient may
be somnolent because of acute-on-chronic hypercapnia. A careful inspection
of the breathing pattern may reveal paradoxical breathing suggestive of di-
aphragmatic dysfunction or impending respiratory failure. Patients who
have OHS are typically rapid shallow breathers during steady state and ta-
chypnea may become even more significant during an exacerbation [19].
Several laboratory findings are supportive of OHS, yet the definitive
test for alveolar hypoventilation is an arterial blood gas performed on
room air. Elevated serum bicarbonate level attributable to metabolic com-
pensation of respiratory acidosis is common in patients who have OHS
and points toward the chronic nature of hypercapnia [21]. Assessment
of the pH helps direct the clinician’s decision on admission to the general
medical floor, noninvasive or step-down respiratory care unit, or ICU. In
general, those who have a pH less than 7.30 should be monitored in an
ICU setting, whereas those who have a pH greater than 7.30 and do
not have significant obtundation can be managed in a noninvasive respi-
ratory care unit or step-down unit with close supervision. Other labora-
tory testing should evaluate for secondary erythrocytosis, severe
hypothyroidism, and drug intoxication. In patients who have cor pulmo-
nale and pulmonary hypertension, chest imaging reveals enlargement of
the cardiac silhouette and prominent pulmonary vascular distribution. In
these patients, an electrocardiogram frequently reveals evidence of right
ventricular hypertrophy and right atrial enlargement, which can be con-
firmed by echocardiography.
538 LEE & MOKHLESI
Once the patient has recovered from the acute exacerbation, a complete
pulmonary function test (PFT) should be performed to exclude other poten-
tial causes of hypercapnia (see Box 1). Common PFT findings in patients
with OHS include a mild to moderate restrictive defect and reduction in ex-
piratory reserve volume attributable to body habitus, accompanied by a nor-
mal FEV1/FVC ratio. Patients who have OHS may also have mild reductions
in maximum expiratory and inspiratory pressures related to the combination
of abnormal respiratory mechanics and weak respiratory muscles [19].
Therapeutic options
In an ICU setting there are several therapeutic modalities that can im-
prove ventilation and oxygenation in patients who have OHS who are expe-
riencing an acute-on-chronic hypercapnic respiratory failure: NPPV,
endotracheal intubation with invasive mechanical ventilation, and tracheos-
tomy with or without mechanical ventilation. Although most of these
patients need supplemental oxygen therapy in addition to positive airway
pressure therapy, supplemental oxygen alone is inadequate and does not
improve ventilation [29]. Continuous positive airway pressure (CPAP), al-
though effective in many patients who have stable OHS [22,30,31], should
not be used in cases of acute-on-chronic hypercapnic respiratory failure
due to its inability to improve alveolar ventilation when compared to NPPV.
Pharmacologic interventions, such as acetazolamide or medroxyproges-
terone, can improve ventilation in some patients when used in conjunction
with positive airway pressure therapy but are ineffective when used as mono-
therapy, particularly in cases of acute-on-chronic hypercapnic respiratory
failure [4]. Phlebotomy has not been systematically studied in patients
who have OHS who develop secondary erythrocytosis. Secondary erythro-
cytosis is a physiologic response to tissue hypoxia to enhance oxygen carry-
ing capacity. Hyperviscosity impairs oxygen delivery, however, and can
counteract the beneficial effects of erythrocytosis. In adult patients who
have congenital cyanotic heart disease, phlebotomy has been recommended
if the hematocrit is greater than 65% only if symptoms of hyperviscosity are
present [32]. It is difficult to extrapolate this recommendation to patients
who have OHS, however, because many symptoms of hyperviscosity are
similar to the symptoms of OHS. Reversing hypoventilation and hypoxemia
with positive airway pressure therapy eventually improves secondary eryth-
rocytosis and phlebotomy is rarely needed in patients who have OHS [33].
Noninvasive positive pressure ventilation

Contrary to eucapnic OSA, effective treatment strategies for OHS must
relieve upper airway obstruction and increase alveolar ventilation. The
therapy of choice for the acutely decompensated patient who has OHS with
hypercapnic respiratory failure is NPPV. NPPV can be applied with volume-
limited, or more commonly, pressure-limited devices (eg, bilevel positive air-
way pressure [bilevel PAP] or pressure support ventilation). Although these
two modes of NPPV have not been compared in patients who have acute-
on-chronic hypercapnic respiratory failure attributable to OHS, both modes
seem to be equally effective in patients who have acute exacerbation of
chronic obstructive pulmonary disease (COPD) and in patients who have
chronic respiratory failure because of restrictive chest wall disorders [34–
37]. Pressure-limited NPPV is easier to tolerate; however, volume-limited
NPPV provides a more stable tidal volume and can generate higher peak
pressures if the patient has higher airway resistance [38,39]. Positive pressure
should be administered during sleep and wakefulness during the acute hos-
pital setting. Bilevel PAP provides inspiratory positive airway pressure
(IPAP) and expiratory positive airway pressure (EPAP), each of which is
set independently. EPAP maintains upper airway patency while the delta be-
tween the IPAP and the EPAP represents pressure support ventilation. In-
creasing the delta therefore leads to larger tidal volumes and increased
ventilation. Given that most patients who have OHS have concomitant se-
vere OSA, the EPAP typically needs to be set at a higher level compared
with patients requiring NPPV because of neuromuscular disease or acute ex-
acerbation of COPD [4]. The decision on pressure- or volume-limited venti-
lation should be based on local expertise and staff familiarity, and should be
tailored to the individual patient [38].
The use of NPPV in patients experiencing acute-on-chronic hypercapnic
respiratory failure associated with OHS is attractive because it improves ven-
tilation and oxygenation, may avoid invasive mechanical ventilation, and is
readily available. The physiologic benefits of NPPV include decreasing the
work of breathing by unloading the respiratory muscles, improving central
chemosensitivity after few days of use, and opening the atelectatic lung regions
[22,24,40]. NPPV, when applied correctly, can acutely improve hypersomno-
lence, dyspnea, and obstructive apneas/hypopneas [6,40,41]. Moreover,
NPPV has a modest beneficial effect on right ventricular function [42].
Long-term therapy in patients who are adherent with NPPV can lead to fur-
ther improvements in gas exchange and increases survival compared with
less adherent patients. Patients who have OHS who used positive airway pres-
sure therapy for more than 4.5 hours per day experienced larger improvement
in PaCO2 and PaO2 compared with less adherent patients (DPaCO2 7.7 versus
2.4 mm Hg, P!.001; DPaO2 9.2 versus 1.8 mm Hg, P!.001) [22]. Recent large
observational studies have reported increased mortality and cardiovascular
morbidity in patients who had severe OSA who were not adherent with posi-
tive airway pressure therapy [43,44]. Although these reports did not exclu-
sively include patients who had OHS, most patients who have OHS do have
severe OSA. The survival benefits of NPPV are sustained at least up to 2 years
in patients who have OHS who are adherent with therapy [13,14].
540 LEE & MOKHLESI
Approach to initiating and monitoring noninvasive positive pressure

ventilation in obesity hypoventilation syndrome
Just as important as recognizing when to initiate NPPV is the recognition
of clinical contraindications that make NPPV unsafe. Clinical criteria
should therefore be established for selecting patients who should be admit-
ted to the ICU and those who should be observed in a step-down respiratory
care unit. More importantly, decisions on where NPPV should be initiated
(emergency room, ICU, or step-down respiratory care unit) should depend
on staff experience and available local resources [45,46]. An appropriately
responsive patient who is hemodynamically stable without life-threatening
arrhythmias can be managed with NPPV in a step-down respiratory care
unit under close nursing and respiratory care supervision [47]. Those indi-
viduals who have a pH less than 7.30, altered mentation, or are intolerant
of NPPV should be directly admitted to the ICU and may require invasive
mechanical ventilation (Boxes 4 and 5).
The importance of careful observation of the acutely hypercapnic obese
patient using NPPV cannot be overemphasized because potential catastro-
phes, such as massive aspiration, unnoticed progressive respiratory failure,
and even death, can result if inadequately supervised. Our experience is sim-
ilar to prior studies that NPPV is as labor intensive as endotracheal intuba-
tion and invasive mechanical ventilation [48]. A multidisciplinary approach
involving skilled nurses, respiratory therapists, and intensivists is therefore
crucial to successful titration of NPPV [46]. In addition, institutions that
have successfully implemented NPPV programs for patients who have
acute-on-chronic hypercapnic respiratory failure have established a central-
ized monitoring unit with a favorable nurse-to-patient ratio to ensure early
recognition of NPPV failure requiring invasive mechanical ventilation.
Several clinical parameters should be monitored frequently during the
first hours of initiating NPPV, such as blood pressure, heart rate, mental sta-
tus, evidence of respiratory distress, oxygen saturation, and arterial blood
gases [47,49]. Successful alveolar ventilation leads to tidal volumes of 8 to
10 mL/kg and decreases the respiratory rate to fewer than 25 breaths per
Box 4. Indications for ICU monitoring in patients

who have obesity hypoventilation syndrome
Significant acute acidemia (pH < 7.30)
Hemodynamic instability or unstable cardiac rhythm
Altered mental status
Multiple organ failuredelevated acute physiology and chronic
health evaluation (APACHE II) or sequential organ failure
assessment (SOFA) score
Intolerance to noninvasive positive pressure ventilation
Box 5. Contraindications to noninvasive positive pressure

ventilation
Hemodynamic instability or unstable cardiac arrhythmia
Inability to protect airway or adequately clear secretions
Active upper gastrointestinal bleeding
Significant abdominal distension
Cerebrovascular accident or intracranial hemorrhage
Interface contraindications
Facial/cranial/eye trauma or recent facial surgery
Persistent epistaxis
Unable to appropriately fit mask
Uncooperative or agitated patient
minute. Arterial blood gases should be followed closely over the first 2 hours
with special attention to pH and PaCO2 trends. Box 6 provides early clinical
markers that indicate NPPV failure and should alert the clinician of impend-
ing respiratory failure. The rate of NPPV failure in patients who have
COPD (not OHS) experiencing an acute hypercapnic respiratory failure
has been reported between 5% and 40% [49]. The best predictor of early
NPPV failure (within the first 1 to 3 hours) was the lack of improvement
in pH and PaCO2 after 1 hour of NPPV [50]. A more recent prospective study
reported an NPPV failure rate of 36% among 33 consecutive morbidly
obese patients developing acute respiratory failure from multiple causes.
In this study, a higher BMI was predictive of NPPV failure (46.9 kg/m2 in
successful NPPV versus 62.5 kg/m2 in NPPV failure) [51]. Ortega Gonzalez
and colleagues [12] did not report any cases of NPPV failure in 17 consec-
utive patients admitted to an ICU with an acute-on-chronic hypercapnic re-
spiratory failure.
Approximately 50% of morbidly obese patients who have acute respira-
tory failure who require emergent endotracheal intubation have a difficult
intubation defined as requiring more than three attempts by experienced cli-
nicians [51,52]. These patients are also at increased risk for peri-intubation
complications, including cardiorespiratory arrest. The clinician planning to
intubate these patients should be cognizant of the limited neck mobility and
the difficulty with visualizing the vocal cords because of the crowded oro-
pharynx [52]. Furthermore, obese patients are at risk for severe oxygen de-
saturation that can occur precipitously because of a lower functional
residual capacity and atelectasis that is exacerbated in the supine position
[19,53]. For these reasons, the most experienced clinician should attempt
to intubate a decompensated patient who has OHS who has failed a trial
of NPPV. Finally, in the difficult airway the clinician may consider placing
a temporary laryngeal mask device or perform intubation with the assis-
tance of a flexible fiberoptic bronchoscope.
542 LEE & MOKHLESI
Box 6. Clinical features suggestive of noninvasive positive

pressure ventilation failure and need for invasive
mechanical ventilation
Deterioration of mental status or psychomotor agitation
pH persistently less than 7.25 or lack of improvement in
hypercapnia after 1 to 2 hours of NPPV
Persistent and refractory hypoxemia
Lack of improvement in tachypnea and dyspnea
Hypotension or bradycardia
Increased use of accessory muscles with impending respiratory
failure
Increased risk for aspiration and inability to clear secretions
Poor tolerance of the interface
Setting up noninvasive positive pressure ventilation equipment: choice

of interface and ventilatory mode
The two most commonly used interfaces are the oronasal mask (full face
mask) or the nasal mask, and an appropriate fitting interface ensures ade-
quate gas exchange without significant leakage. Oronasal masks are usually
recommended in acutely ill patients because they allow the delivery of higher
pressures with less leakage and permit mouth breathing [38]. Unfortunately
full-face interfaces can be uncomfortable and it is difficult for patients to
communicate or eat. Nasal masks can be more comfortable and better tol-
erated especially in the claustrophobic patient, but to achieve adequate pres-
sure delivery, a closed mouth is required. One small study found that in
stable patients who had chronic hypercapnic respiratory failure, NPPV ap-
plied through an oronasal mask was slightly more effective in lowering the
PaCO2 because of an increase in the tidal volume compared with nasal masks
[54]. Patients experiencing an acute-on-chronic hypercapnic respiratory fail-
ure tend to perform a significant amount of mouth breathing, therefore in
this setting an oronasal mask is advisable [38]. The interface can be later
switched to a nasal mask once the patient is more stable and if prolonged
NPPV is deemed necessary. The choice of interface should be highly individ-
ualized; to establish an effective NPPV protocol it is imperative to have
a wide variety of interfaces available. If a patient has been previously fitted
with a mask as an outpatient, then that particular type of mask could be
used. The mask should be secured firmly with a head strap but excessive
tightening should be avoided because it can increase leakage.
Pressures should be titrated slowly to allow the patient to acclimate to the
device. Careful attention should be paid to nasal passage drying, nasal
bridge skin breakdown, or discomfort from an improperly fitting mask.
Heated humidity can prevent drying of the nasal passages and a hydrocolloid
dressing can be applied at the nasal bridge to prevent ulceration [38].
Pressure-limited NPPV can be delivered by conventional modern ventila-
tors that provide biphasic positive airway pressure ventilation or by way of
bilevel PAP generators. Volume preset ventilators can be used for NPPV
also based on availability and local expertise. Given that pressure-limited
NPPV is easier to tolerate [39], bilevel PAP should be considered first-line
therapy for noninvasive support in patients who have OHS experiencing
an acute-on-chronic hypercapnic respiratory failure. Pressure settings
should be tailored to each patient; however, a reasonable starting point in-
cludes an EPAP set at 5 cm H2O and the IPAP set at 10 cm H2O. A repet-
itive cyclical pattern of oxygen desaturationdmeasured by pulse oximetry
(SpO2)dis typically associated with obstructive apneas and hypopneas.
With real-time monitoring of the pulse oximetry tracing, the EPAP can be
gradually increased until the disappearance of repetitive dips in SpO2 and
resolution of clinically apparent apneas or snoring during sleep. The
IPAP can then be increased until there is an acceptable level of steady oxy-
genation (SpO2O92%) suggestive of an improvement in ventilation. In
studies that have reported significant improvement in hypercapnia and hyp-
oxia with bilevel PAP therapy, the IPAP was at least 8 to 10 cm H2O greater
than EPAP to achieve adequate ventilation [6,55]. Patients who have acute-
on-chronic hypercapnic respiratory failure attributable to OHS typically re-
quire high IPAP (mean of 18 cm H2O; range 12–30 cm H2O) and EPAP
(mean of 9 cm H2O; range 5–13 cm H2O) [6,12]. Despite delivering high pos-
itive airway pressure many of these patients remain hypoxic and require the
addition of supplemental oxygen to positive airway pressure therapy
(Fig. 2). Although the maximal amount of inspiratory pressure necessary
or tolerated in patients who have OHS with acute-on-chronic hypercapnic
respiratory failure has not been systematically studied, in general patients
have difficulty tolerating IPAP greater than 20 cm H2O. Similarly, patients
who have COPD exacerbation or chest wall deformity had little to be gained
by increasing inspiratory pressures more than 25 cm H2O [56].
Initially NPPV should be continuous during nighttime and during the day.
Patients should be given breaks to allow eating or communication with fam-
ily. Concurrent therapy for cor pulmonale should be initiated with diuretics
and supplemental oxygen. Some patients may not reach eucapniadreflecting
chronic respiratory acidosisdtherefore following the pH may be the
best marker of acute clinical improvement. Patients should be expected to
improve within 1 to 3 hours of therapy, with most patients who have
OHS reaching near-normal pH within 12 to 24 hours. Acute-on-chronic hy-
percapnic respiratory failure in patients who have OHS resolves more rap-
idly compared with patients who have COPD and congestive heart failure
[12]. Once acid–base stability is achieved (a persistent pH greater than
7.35) then daytime NPPV can be discontinued, yet nighttime support
should be continued.
544 LEE & MOKHLESI
OHS risk factors? Unstable medical status?

BMI 35 kg/m2 pH < 7.25 Transfer to ICU
Yes Yes
PaCO2 45 mm Hg Altered mental status Consider invasive
History suggestive of sleep- Hemodynamic instability mechanical ventilation
disordered breathing Multi-organ failure
No
Contraindications to NPPV?
Hemodynamic instability
Inability to protect airway
Unable to clear secretions
Psychomotor agitation Yes
Stroke
Upper gastrointestinal bleeding
Abdominal distention
Unable to properly fit interface
Interface intolerance
No
Initiating and monitoring NPPV in a respiratory care unit or ICU

Closely monitor respiratory rate, heart rate, blood pressure, oxygen saturation, and
mental status
Reassess arterial blood gases in 1-2 hours
Favorable nurse or respiratory therapist to patient ratio
Interface–Start with oronasal mask and if intolerant use nasal mask
Bi-level PAP titration
EPAP: Start at 5 cm H2O
Increase by 2 cm H2O to alleviate clinically obvious apneas,
snoring, and repetitive SpO2 desaturations
IPAP: Start at 10 cm H2O
Increase by 2 cm H2O to improve a steady SpO2 at 92
IPAP typically needs to be at least 8 to 10 cm H2O above EPAP to
achieve adequate ventilation in OHS
Add supplemental oxygen to bi-level PAP to keep SpO2 92
Goals achieved?
Decrease work of breathing (RR < 25 breaths/min) No
Improvement in acidosis and hypercapnia within 1-2 h
Sustained improvement in hypoxia (SpO2 92 )
Yes
Continue NPPV
NPPV should be continuous during day and night
Breaks to allow eating or communication
Most OHS patients reach near normal pH within
12-24 h of NPPV
Fig. 2. Management of patients who have OHS requiring hospitalization because of acute-on-
chronic hypercapnic respiratory failure.
The use of medications that may further exacerbate hypoventilation, es-

pecially sedative-hypnotic or narcotic agents, should be limited. In addition
patients who have OHS are at high risk for thromboembolic diseases [10,11];
therefore adequate deep vein thrombosis prophylaxis is essential. Finally,
elevating the head of the bed can decrease the risk for aspiration and may
decrease the pressure required to resolve obstructive apneas, hypopneas,
and hypoventilation [57,58].
In follow-up, an outpatient polysomnogram with positive airway pres-

sure titration should be performed after discharge from the hospital.
Many patients who have OHS who initially require bilevel PAP can be
switched to CPAP after the resolution of hypercapnia [6,59]. Furthermore,
with adequate adherence with positive airway pressure therapy long-term
supplemental oxygen can be discontinued in many patients [22].
Tracheostomy
Tracheostomy should be reserved for patients who have refractory OHS
who have failed other modes of ventilatory support, are intolerant of NPPV,
have severe cor pulmonale, or have a longstanding history of nonadherence
with outpatient NPPV therapy. Tracheostomy may also become necessary
in a subset of patients who cannot be successfully extubated and liberated
from invasive mechanical ventilation. Tracheostomy bypasses the crowded
upper airway and can substantially decrease apneas and hypopneas in pa-
tients who have uncomplicated OSA. In patients who have OHS tracheos-
tomy can lead to improvement but not complete resolution of sleep-
disordered breathing. Nevertheless, the improvement in the severity of
sleep-disordered breathing after tracheostomy can lead to the resolution
of hypercapnia [60]. The clinician should be aware of anatomic characteris-
tics of obesity that make tracheostomy technically challenging. An inferiorly
located larynx creates the potential for postoperative vascular complications
because the tracheostomy tube is closer to the great vessels of the chest, and
thick layers of adipose tissue within the tracheostomy site may stimulate
increased production of granulation tissue leading to infection and bleeding
[61]. Tracheostomy should be performed by an experienced otolaryngologist
in carefully selected patients.
Discusssion
Because of the global obesity epidemic and the high prevalence of OSA in
the general population, critical care physicians are likely to encounter patients
who have acute-on-chronic hypercapnic respiratory failure attributable to
OHS in their clinical practice. We believe that early recognition of OHS leads
to effective treatment and likely results in a decrease in morbidity and mortal-
ity. In the ICU setting, implementation of NPPV has marked beneficial effects
leading to improvement in alveolar ventilation, hypercapnia, and hypoxia,
and can avoid the need for endotracheal intubation and invasive mechanical
ventilation. It is essential for these patients to be discharged from the ICU
on adequate NPPV therapy. Ultimately, the improvements in outcomes are di-
rectly related to adherence with positive airway pressure therapy. Early outpa-
tient follow-up is therefore imperative and should include repeat measurement
of arterial blood gases and objective assessment of adherence with therapy be-
cause patients frequently overestimate adherence.
546 LEE & MOKHLESI
Summary
OHS is characterized by obesity (BMI R 30 kg/m2), daytime hypercap-

nia (PaCO2 R 45 mm Hg), and sleep-disordered breathing in the absence
of other known causes of hypercapnia.
Patients who have OHS have increased health care resources use and
require more frequent hospitalization because of dyspnea or acute-on-
chronic hypercapnic respiratory failure compared with patients who
have similar degrees of obesity.
The pathophysiology of OHS is multifactorial and includes abnormal
respiratory system mechanics attributable to obesity, blunted central re-
sponse to hypercapnia and hypoxia, sleep-disordered breathing, and
neurohormonal abnormalities, such as leptin resistance.
NPPV with bilevel PAP is the treatment of choice in acute and chronic
hypercapnic respiratory failure in patients who have OHS.
Management of acute-on-chronic hypercapnic respiratory failure can be
performed in a respiratory care unit with close nursing supervision,
a dedicated management plan, and careful recognition of progressive re-
spiratory failure requiring invasive mechanical ventilation.
Significant weight loss, typically by weight reduction surgery, or long-
term adherence with positive airway pressure therapy (CPAP or bilevel
PAP) are the therapeutic options that will ultimately improve the high
morbidity and mortality associated with OHS.
References
[1] Auchincloss JH Jr, Cook E, Renzetti AD. Clinical and physiological aspects of a case of
obesity, polycythemia and alveolar hypoventilation. J Clin Invest 1955;34:1537–45.
[2] Burwell CS, Robin ED, Whaley RD, et al. Extreme obesity associated with alveolar
hypoventilation: a Pickwickian syndrome. Am J Med 1956;21:811–8.
[3] Sleep-related breathing disorders in adults: recommendations for syndrome definition and
measurement techniques in clinical research. The report of an American Academy of Sleep
Medicine Task Force. Sleep 1999;22:667–89.
[4] Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007;
132:1322–36.
[5] Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome
revisited: a prospective study of 34 consecutive cases. Chest 2001;120:369–76.
[6] Perez de Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal
intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome.
Chest 2005;128:587–94.
[7] Berg G, Delaive K, Manfreda J, et al. The use of health-care resources in obesity-
hypoventilation syndrome. Chest 2001;120:377–83.
[8] Nowbar S, Burkart KM, Gonzales R, et al. Obesity-associated hypoventilation in hospital-
ized patients: prevalence, effects, and outcome. Am J Med 2004;116:1–7.
[9] Quint JK, Ward L, Davison AG. Previously undiagnosed obesity hypoventilation syn-
drome. Thorax 2007;62:462–3.
[10] MacGregor MI, Block AJ, Ball WC Jr. Topics in clinical medicine: serious complications
and sudden death in the Pickwickian syndrome. Johns Hopkins Med J 1970;126:279–95.
[11] Miller A, Granada M. In-hospital mortality in the Pickwickian syndrome. Am J Med 1974;
56:144–50.
[12] Ortega Gonzalez A, Peces-Barba Romero G, Fernandez Ormaechea I, et al. Evolution of
patients with chronic obstructive pulmonary disease, obesity hypoventilation syndrome or
congestive heart failure in a respiratory monitoring unit. Arch Bronconeumol 2006;42:423–9.
[13] Heinemann F, Budweiser S, Dobroschke J, et al. Non-invasive positive pressure ventilation
improves lung volumes in the obesity hypoventilation syndrome. Respir Med 2007;101:
1229–35.
[14] Budweiser S, Riedl SG, Jorres RA, et al. Mortality and prognostic factors in patients with
obesity-hypoventilation syndrome undergoing noninvasive ventilation. J Intern Med 2007;
261:375–83.
[15] Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005;118:948–56.
[16] Sharp JT, Henry JP, Sweany SK, et al. The total work of breathing in normal and obese men.
J Clin Invest 1964;43:728–39.
[17] Sampson MG, Grassino K. Neuromechanical properties in obese patients during carbon
dioxide rebreathing. Am J Med 1983;75:81–90.
[18] Kress JP, Pohlman AS, Alverdy J, et al. The impact of morbid obesity on oxygen cost of
breathing (VO2RESP) at rest. Am J Respir Crit Care Med 1999;160:883–6.
[19] Koenig SM. Pulmonary complications of obesity. Am J Med Sci 2001;321:249–79.
[20] Laaban JP, Chailleux E. Daytime hypercapnia in adult patients with obstructive sleep apnea
syndrome in France, before initiating nocturnal nasal continuous positive airway pressure
therapy. Chest 2005;127:710–5.
[21] Mokhlesi B, Tulaimat A, Faibussowitsch I, et al. Obesity hypoventilation syndrome:
prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007;11:
117–24.
[22] Mokhlesi B, Tulaimat A, Evans AT, et al. Impact of adherence with positive airway pressure
therapy on hypercapnia in obstructive sleep apnea. J Clin Sleep Med 2006;2:57–62.
[23] Rapoport DM, Garay SM, Epstein H, et al. Hypercapnia in the obstructive sleep apnea
syndrome. A reevaluation of the ‘‘Pickwickian syndrome’’. Chest 1986;89:627–35.
[24] Han F, Chen E, Wei H, et al. Treatment effects on carbon dioxide retention in patients with
obstructive sleep apnea-hypopnea syndrome. Chest 2001;119:1814–9.
[25] Leech JA, Onal E, Lopata M. Nasal CPAP continues to improve sleep-disordered breathing
and daytime oxygenation over long-term follow-up of occlusive sleep apnea syndrome.
Chest 1992;102:1651–5.
[26] Berger KI, Ayappa I, Chatr-Amontri B, et al. Obesity hypoventilation syndrome as
a spectrum of respiratory disturbances during sleep. Chest 2001;120:1231–8.
[27] Masa JF, Celli BR, Riesco JA, et al. The obesity hypoventilation syndrome can be treated
with noninvasive mechanical ventilation. Chest 2001;119:1102–7.
[28] de Lucas-Ramos P, de Miguel-Diez J, Santacruz-Siminiani A, et al. Benefits at 1 year of
nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation
syndrome. Respir Med 2004;98:961–7.
[29] Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not
oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest
1997;112:207–13.
[30] Banerjee D, Yee BJ, Piper AJ, et al. Obesity hypoventilation syndrome: hypoxemia during
continuous positive airway pressure. Chest 2007;131:1678–84.
[31] Mokhlesi B. Positive airway pressure titration in obesity hypoventilation syndrome:
continuous positive airway pressure or bilevel positive airway pressure. Chest 2007;131:
1624–6.
[32] Thorne SA. Management of polycythaemia in adults with cyanotic congenital heart disease.
Heart 1998;79:315–6.
548 LEE & MOKHLESI
[33] Heinemann F, Budweiser S, Dobroschke J, et al. Non-invasive positive pressure ventilation

improves lung volumes in the obesity hypoventilation syndrome. Respir Med 2007;101:
1229–35.
[34] Meecham Jones DJ, Paul EA, Grahame-Clarke C, et al. Nasal ventilation in acute exacerba-
tions of chronic obstructive pulmonary disease: effect of ventilator mode on arterial blood
gas tensions. Thorax 1994;49:1222–4.
[35] Vitacca M, Rubini F, Foglio K, et al. Non-invasive modalities of positive pressure ventila-
tion improve the outcome of acute exacerbations in COLD patients. Intensive Care Med
1993;19:450–5.
[36] Tuggey JM, Elliott MW. Randomised crossover study of pressure and volume non-invasive
ventilation in chest wall deformity. Thorax 2005;60:859–64.
[37] Windisch W, Storre JH, Sorichter S, et al. Comparison of volume- and pressure-limited
NPPV at night: a prospective randomized cross-over trial. Respir Med 2005;99:52–9.
[38] International Consensus Conferences in Intensive Care Medicine: noninvasive positive pres-
sure ventilation in acute respiratory failure. Am J Respir Crit Care Med 2001;163:283–91.
[39] Schonhofer B, Sonneborn M, Haidl P, et al. Comparison of two different modes for nonin-
vasive mechanical ventilation in chronic respiratory failure: volume versus pressure
controlled device. Eur Respir J 1997;10:184–91.
[40] Pankow W, Hijjeh N, Schuttler F, et al. Influence of noninvasive positive pressure ventilation
on inspiratory muscle activity in obese subjects. Eur Respir J 1997;10:2847–52.
[41] Waldhorn RE. Nocturnal nasal intermittent positive pressure ventilation with bi-level
positive airway pressure (BiPAP) in respiratory failure. Chest 1992;101:516–21.
[42] Nahmias J, Lao R, Karetzky M. Right ventricular dysfunction in obstructive sleep apnoea:
reversal with nasal continuous positive airway pressure. Eur Respir J 1996;9:945–51.
[43] Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with
obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive
airway pressure: an observational study. Lancet 2005;365:1046–53.
[44] Campos-Rodriguez F, Pena-Grinan N, Reyes-Nunez N, et al. Mortality in obstructive sleep
apnea-hypopnea patients treated with positive airway pressure. Chest 2005;128:624–33.
[45] Paus-Jenssen ES, Reid JK, Cockcroft DW, et al. The use of noninvasive ventilation in acute
respiratory failure at a tertiary care center. Chest 2004;126:165–72.
[46] Elliott MW, Confalonieri M, Nava S. Where to perform noninvasive ventilation? Eur Respir
J 2002;19:1159–66.
[47] Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerba-
tions of chronic obstructive pulmonary disease on general respiratory wards: a multicentre
randomised controlled trial. Lancet 2000;355:1931–5.
[48] Nava S, Evangelisti I, Rampulla C, et al. Human and financial costs of noninvasive mechan-
ical ventilation in patients affected by COPD and acute respiratory failure. Chest 1997;111:
1631–8.
[49] Nava S, Ceriana P. Causes of failure of noninvasive mechanical ventilation. Respir Care
2004;49:295–303.
[50] Anton A, Guell R, Gomez J, et al. Predicting the result of noninvasive ventilation in severe
acute exacerbations of patients with chronic airflow limitation. Chest 2000;117:828–33.
[51] Duarte AG, Justino E, Bigler T, et al. Outcomes of morbidly obese patients requiring
mechanical ventilation for acute respiratory failure. Crit Care Med 2007;35:732–7.
[52] Paix AD, Williamson JA, Runciman WB. Crisis management during anaesthesia: difficult
intubation. Qual Saf Health Care 2005;14:e5–6.
[53] Walz JM, Zayaruzny M, Heard SO. Airway management in critical illness. Chest 2007;131:
608–20.
[54] Navalesi P, Fanfulla F, Frigerio P, et al. Physiologic evaluation of noninvasive mechanical
ventilation delivered with three types of masks in patients with chronic hypercapnic respira-
tory failure. Crit Care Med 2000;28:1785–90.
[55] Rabec C, Merati M, Baudouin N, et al. (Management of obesity and respiratory insuffi-
ciency. The value of dual-level pressure nasal ventilation). Rev Mal Respir 1998;15:269–78
[in French].
[56] Tuggey JM, Elliott MW. Titration of non-invasive positive pressure ventilation in chronic
respiratory failure. Respir Med 2006;100:1262–9.
[57] Chiu KL, Ryan CM, Shiota S, et al. Fluid shift by lower body positive pressure increases
pharyngeal resistance in healthy subjects. Am J Respir Crit Care Med 2006;174:1378–83.
[58] Shiota S, Ryan CM, Chiu KL, et al. Alterations in upper airway cross-sectional area in
response to lower body positive pressure in healthy subjects. Thorax 2007;62:868–72.
[59] Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe
obstructive sleep apnea and hypercapnia. Chest 1994;105:434–40.
[60] Kim SH, Eisele DW, Smith PL, et al. Evaluation of patients with sleep apnea after tracheot-
omy. Arch Otolaryngol Head Neck Surg 1998;124:996–1000.
[61] McLear PW, Thawley SE. Airway management in obesity hypoventilation syndrome. Clin
Chest Med 1991;12:585–8.
Crit Care Clin 24 (2008) 551–563
The Overlap Syndrome: Chronic

Obstructive Pulmonary Disease
and Obstructive Sleep Apnea
David Hiestand, MD, PhDa,
Barbara Phillips, MD, MSPHa,*
a
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky College
of Medicine, K528 Kentucky Clinic, 740 South Limestone Street, Lexington, KY 40536, USA
The ‘‘overlap syndrome’’ is a commonly used term identifying several

pairs of disorders in medicine. In the context of this article, it defines the
relationship between obstructive sleep apnea (OSA) and chronic obstructive
pulmonary disease (COPD), a commonly noted but poorly studied disorder.
The syndrome was initially described in 1985 by Flenley [1] to express the
relationship between COPD and OSA. Flenley pointed out that the clinical
presentation of this syndrome is different from usual OSA primarily in that
sleep-related hypoxemia is more severe. In his study, patients had relatively
severe COPD. Since the original description, individuals who have the over-
lap syndrome have been recognized to have greater risk for pulmonary hy-
pertension [2], right heart failure [3], and hypercapnia [4] than patients who
have either disorder alone. Furthermore, such complications develop earlier
in patients who have COPD with OSA than in those who do not have OSA.
The combined effects of COPD and OSA resulting in the overlap syn-
drome produce more significant sleep-associated breathing problems than
simple sleep-associated hypoxemia seen in COPD. Sleep-associated hypox-
emia associated with COPD was initially documented by Trask and Cree
[5] in 1962, but increasing use of transcutaneous pulse oximetry with poly-
somnography in the late 1970s and 1980s resulted in further characteriza-
tion. These studies also revealed that oxyhemoglobin desaturations were
worse in rapid eye movement (REM) than non-REM sleep [6–8]. Supple-
mental oxygen was demonstrated to treat oxygen desaturations and improve
sleep quality in such patients [9,10].
E-mail address: bphil95@aol.com (B. Phillips).
552 HIESTAND & PHILLIPS
The traits possessed by those who have the overlap syndrome were
the classic ‘‘blue bloater’’ phenotype of COPD, in which obesity and snoring
are relatively common. Individuals who had this syndrome also had morning
headache and the potential for development of hypercapnia when treated
with oxygen. These patients demonstrated clinical improvement with
positive airway pressure and had limited symptomatic improvement with
supplemental oxygen. In contrast, individuals who had the ‘‘pink puffer’’
phenotype of COPD did not typically demonstrate obstructive apneas or hy-
popneas and responded well to supplemental oxygen but not to positive air-
way pressure.
The overlap syndrome, by virtue of the relative high prevalence of OSA
and COPD in the population, is believed to be prevalent in sleep and pulmo-
nary clinics. In actuality, data about the overlap syndrome are sparse, partic-
ularly for those patients who have less severe COPD. This deficiency in the
literature is important, because it is unclear if patients who have mild
COPD are at risk for the same early complications as those who have
more severe disease. Similarly, the significance of mild versus severe OSA is
unknown as it relates to complications, course, and prognosis of the
syndrome.
Epidemiology
The prevalence of COPD is varied based on population, definition, and
methodology used. The recently published BOLD (Burden of Obstructive
Lung Disease) study [11] provides insight into the worldwide prevalence
of the disease. This study was a 12-center, international study of 9425 indi-
viduals who completed post-bronchodilator spirometry testing along with
questionnaires about respiratory symptoms, health status, and exposure to
COPD risk factors. In this study the prevalence of GOLD (Global Initiative
for Chronic Obstructive Lung Disease) stage II or higher COPD was 10.1%,
with a slight male predominance (11.8% versus 8.5%) [11]. This study con-
firms meta-analyses completed by Halbert in 2003 and 2006 [12,13], in which
COPD prevalence in the adult population was in the 5% to 10% range.
Because many of these patients have relatively mild disease, with FEV1%
predicted from 50% to 80% (stage II), this likely does not represent the pro-
portion of the population at risk for the syndrome as described by Flenley.
The prevalence of GOLD stage III and IV disease (FEV1% predicted 50%),
wherein chronic or intermittent hypoxemia and hypercapnia are more com-
mon, is in the range of 3% to 4% and likely represents the segment of the
COPD population at risk for the complications of overlap syndrome as cur-
rently described.
The prevalence of OSA is similarly varied based on definition used and
population studied. Risk factors for OSA, such as obesity, snoring, and day-
time sleepiness, are increasingly common. The classic and most commonly
quoted study of the prevalence of sleep-disordered breathing in the United
THE OVERLAP SYNDROME 553
States by Young and colleagues [14] identifies a prevalence of 4% of men

and 2% of women aged 35 to 60. These data, from the Wisconsin Sleep
Cohort, represent individuals who have an apnea-hypopnea index (AHI)
greater than or equal to 5 and daytime sleepiness. Because patients both un-
derreport and overreport sleepiness [15], the validity of this definition has
been called into question. From the Sleep Heart Health Study, 22% of
subjects had a respiratory disturbance index of greater than or equal to
15 events per hour [16], clearly a significant proportion of the population.
Considering such variation in individual studies, a comprehensive review
and analysis of available data by Young and colleagues [17] places the prev-
alence at 5% of adults in developed countries, and this is now a commonly
accepted prevalence for the disease (the definition did include sleepiness). An
accurate assessment of prevalence by severity of disease cannot at this time
be made.
Although several studies provided data for the prevalence of the individ-
ual disease, there are no large prevalence studies of the overlap syndrome.
This lack of studies is likely because of methodologic limitations, including
absence of a diagnostic code for the syndrome and absence of data in large
cohort studies completed in the past. There are several small epidemiologic
analyses from the United States and overseas indicating increased preva-
lence of OSA in individuals who have COPD [18]. There seems to be an
increased prevalence of COPD in individuals who have OSA also [4,19].
In the Chaouat and colleagues study [19], 11% of 265 patients who had
OSA were found to have an obstructive pattern on spirogram. The degree
of clinical disease in these patients is unclear, however.
Data from the Sleep Heart Health Study represent the largest investiga-
tion to date, and include an analysis of 1132 subjects [20]. Of the study pop-
ulation (n ¼ 5954), 1132 participants had obstructive airways disease as
defined by an FEV1/FVC ratio of less than 70%. The authors of this study
concluded that the airflow obstruction was, in general, mild based on
a mean FEV1/FVC ratio of 63.8%. Because the authors of this study do
not report FEV1, it is difficult to discern the true severity of disease in
this population based on FEV1. Furthermore, this method of evaluating
the degree of airflow obstruction becomes more complex with increasing
obesity. In patients who have marked obesity (who are at greatest risk for
OSA), FVC declines, typically producing a restrictive spirogram. Individ-
uals who have ‘‘normal’’ FEV1/FVC ratios could thus be misclassified as
normal and have significant clinical COPD. In the context of these limita-
tions, OSA was not more prevalent in patients who had COPD than those
who did not [20]. OSA occurred in 22% of participants who had COPD
versus 29% of those who did not have COPD. Sleep-related desaturations
were more severe in COPD patients who had OSA than those who did
not. Because of the limitations of this study, however, more data are needed
to fully delineate the true prevalence of the overlap syndrome in each
population.
Disturbances in ventilation
Hypoxemia
Transient hypoxemia during sleep is not uncommon in patients who have
COPD; this was described as early as the 1960s. This hypoxemia, however,
does not represent the sleep apnea–hypopnea syndrome in the form of poly-
somnography-defined apneas and hypopneas [21]. In this small study of
20 patients who had COPD and 20 age-matched healthy subjects, apneas
and hypopneas were rare in the non-obese COPD group.
The worsening hypoxemia seen at night in COPD patients who do not
have OSA is attributable to a combination of alveolar hypoventilation
and ventilation-perfusion (V/Q) mismatching. Alveolar hypoventilation
represents the predominant mechanism, especially when individuals are in
REM sleep in which hypoventilation is common in normal controls.
Hypoxemia is also well described in OSA. The hypoxemic events in these
individuals are closely associated with apneas and hypopneas, and result
from alveolar hypoventilation. In the absence of coexisting disease, disor-
ders with right-to-left shunt or significant V/Q mismatch, individuals have
normal oxygen saturation between respiratory events.
Hypoxemia in patients who have the overlap syndrome is more signifi-
cant than that seen in either individual syndrome. These patients typically
have baseline arterial oxygen saturation (SaO2) levels lower than normal
individuals, and the greatest predictor of nocturnal hypoxemia is daytime
hypoxemia [22]. This finding is easily explained by the characteristics of
the oxyhemoglobin dissociation curve. Assuming a pH of 7.4, temperature
of 37 C, and PaCO2 of 40 mm Hg, at PaO2 of 85 mm Hg (normal), a decrease
in PaO2 of about 21 mm Hg is needed to produce an SaO2 reduction of 4%.
If PaO2 is 55 mm Hg, however, a 15 mm Hg decrease in PaO2 results in
a 15% decrease in the SaO2. Patients who have the overlap syndrome thus
are likely to have marked decreases in SaO2 with apneas and hypopneas.
Patients who have the overlap syndrome thus suffer from the chronic
hypoventilation and V/Q mismatch associated with COPD and the acute
apneic desaturations associated with OSA.
Hypercapnia
Though hypoxemia is rare during sleep in normal individuals who do not
have COPD, OSA, or other conditions associated with shunting of V/Q mis-
match, a degree of hypercapnia occurs even in normal individuals during
sleep. Minute ventilation and ventilatory responsiveness to CO2 progres-
sively decrease as the depth of sleep increases. This finding is demonstrated
in several studies of varied quality, which all showed that in EEG-
documented sleep the slope of the ventilation-CO2 response decreases during
non-REM sleep and is more blunted in REM sleep [23–26]. This finding
results from a change in the brainstem responsiveness to hypercapnia in
non-REM and REM sleep. Patients who have COPD, having a mechanical
disadvantage to increased tidal volume because of flattened diaphragms,
demonstrate a more pronounced hypercapnic response during sleep. Patients
who have concomitant OSA have episodic hypercapnic events resulting from
apneas and hypopneas and leading to arousals with stimulation to increase
ventilation. The arousal response is variable between individuals, but typi-
cally induces an arousal when end tidal carbon dioxide (ETCO2) increases
by 15 mm Hg or more.
Consequences
Inflammation
Increasing data suggest inflammatory mediators are elevated in OSA,
particularly those mediators associated with cardiovascular risk. Significant
elevation in nuclear factor kB (NF-kB) [27], tumor necrosis factor, interleu-
kin-6, C-reactive protein [28], and homocysteine [29] are seen in patients
who have OSA compared with normal controls. Such elevations are postu-
lated to have a role in the increased cardiovascular risk seen in patients who
have OSA.
A relationship between COPD and cardiovascular risk has also been pos-
tulated [30]. Data from the Framingham Heart Study support this associa-
tion, with a recent analysis demonstrating a positive link connecting
systemic inflammation and lower levels of lung function [31]. COPD is an
inflammatory airways disorder, and with the inflammatory mediator eleva-
tion seen in COPD, coexistent OSA could lead to deterioration of COPD.
It is unclear whether the overlap syndrome carries additive or synergistic
consequences of the inflammatory consequences of these two disorders. One
rational and postulated mechanism of inflammation is hypoxemia. Further
study is needed to define these relationships and define whether they are
causative or correlative with regard to the individual disorders or the
syndrome.
Quality of sleep
The quality of sleep is noted to be poorer in patients who have COPD
and OSA. There are few data, however, on patients who have the overlap
syndrome.
Insomnia has been reported in patients who have COPD. In a study by
Klink and colleagues [32], insomnia was reported in 39% of patients who
had cough or wheezing present and in 53% if both were present. Objective
evidence of disturbed sleep in patients who have COPD has also been dem-
onstrated, with reduced sleep efficiency and total sleep time, delay in sleep
onset, and increased wake after sleep onset [9,10,33].
Similarly, insomnia is well described in patients who have OSA, and sleep
disruption is a hallmark of OSA, particularly in those who have more severe
disease and in women [34], whose prevalence of COPD is still increasing.

Treatment of OSA seems to improve both subjective and objective sleep.
The limited data available on individuals who have the overlap syndrome
have not shown significant sleep disturbance in individuals who have COPD
who do not have OSA as compared with control patients. In the absence of
OSA, after adjusting for age, sex, height, weight, race, and smoking status,
there were statistically significant but small differences between patients who
did and did not have COPD with regard to total sleep time [20]. No differ-
ences were observed with regard to Epworth Sleepiness Score, sleep latency,
sleep efficiency, arousal index, or percent of total sleep time spent in individ-
ual sleep stages. Based on the available data, therefore, it seems that neither
subjective nor objective sleep is more adversely affected in the overlap syn-
drome than in either disease alone.
Pulmonary hemodynamics
Pulmonary hemodynamics have been studied in patients who have COPD
and those who have OSA, with both disorders being associated with variable
degrees of pulmonary hypertension, potentially linked to severity of disease.
Several studies of patients who have the overlap syndrome have included as-
sessments of pulmonary pressure, although these studies are generally small.
Data on pulmonary hemodynamics in COPD date back to the late 1970s,
when Coccagna and Lugaresi published their study of 12 patients who had
severe COPD and daytime pulmonary hypertension. In this group the mean
pulmonary artery pressure increased from 37 mm Hg during wakefulness to
55 mm Hg during REM sleep. PaO2 decreased from 56 to 43 mm Hg from
wakefulness to REM. Similar but less significant findings have been seen in
patients who had slightly less severe COPD [35,36]. In each of these studies,
patients had significant COPD with diurnal hypoxemia. This phenomenon
was not demonstrated in a relatively large (n ¼ 105 patients) study of
patients who did not have daytime hypoxemia [37]. The mechanism of pul-
monary pressure elevation therefore seems to be relatively severe hypoxemia
and not the inflammatory aspect of COPD.
The relationship between pulmonary hypertension and OSA has been the
subject of recently published practice guideline by the American College of
Chest Physicians [38]. In this guideline, 12 studies were identified estimating
the prevalence of pulmonary hypertension in OSA. Methodologic differ-
ences limit direct comparison of these studies, however; in general patients
who had pulmonary hypertension were older, heavier, and had worse lung
function that those who did not have pulmonary hypertension. The degree
of sleep apnea based on AHI was a weak predictor of pulmonary arterial
hypertension (PAH), whereas nocturnal desaturation was a more significant
determinant of the presence of PAH.
The limited data on pulmonary pressure in patients who have the overlap
syndrome suggest elevations in pulmonary pressure, but no studies have
been conducted on patients who have the overlap syndrome controlling for
hypoxemia. It is thus likely that significant diurnal hypoxemia is the under-
lying mechanism for pulmonary hypertension, with less of a contribution
from the underlying mechanism from COPD or OSA.
Cardiac disease and arrhythmia

Cardiac rhythm disturbances have been associated with OSA and COPD.
In patients who have COPD, premature ventricular contractions have been
observed to be common in sleep particularly in those who have nocturnal
SaO2 less than 80% [39,40]. In patients who have OSA, more significant
arrhythmias have been noted. A recent review summarizes the spectrum
of cardiac arrhythmias and potential mechanisms involved [41]. In contrast
to patients who have COPD, the entire spectrum of cardiac arrhythmias has
been observed in patients who have OSA. The risk for manifesting a cardiac
arrhythmia seems to be related to the severity of disease. The most common
abnormality, seen in virtually all patients who have severe OSA, is marked
sinus arrhythmia, characterized by bradycardia during apnea, followed by
tachycardia on resumption of respiration. OSA is also an independent
risk factor for atrial fibrillation [42,43], an arrhythmia that is common in
the COPD population.
No specific studies have been conducted on cardiac arrhythmias in patients
who have the overlap syndrome. A postulated, but unproven, theory is that
rhythm disturbances should be worse in these individuals as a result of more
profound hypoxemia. Studies controlling for hypoxemia in patients who
have the overlap syndrome need to be conducted to confirm this hypothesis.
Quality of life
A single study has addressed health-related quality of life in patients who
have the overlap syndrome. Mermigkis and colleagues [44] evaluated 30 sub-
jects who had the overlap syndrome and 15 control subjects. The subjects
were similar in age, body mass index (BMI), airflow obstruction, spirometry
values, daytime sleepiness by Epworth, PO2, and PCO2. Those who had the
overlap syndrome had significantly elevated St. George’s respiratory ques-
tionnaire scores for total score and for each of the three components as com-
pared with patients who had COPD alone.
Mortality
Mortality specific to the overlap syndrome has not been studied directly
because of lack of a defined cohort, absence of a diagnostic code for the
overlap syndrome, and incomplete data in many of the large previously
designed cohorts. There are some data supporting an increase in mortality
in patients who have untreated OSA, with most of this increase attributed
to cardiovascular causes [45–48]. COPD mortality is well studied, with the
most recent data identifying a death rate of 56.7/100,000 in women and

82.6/100,000 in men (2002) [49]. Although not studied as an overlap syn-
drome cohort, Lavie and colleagues [50] recently published data on a cohort
of patients who had sleep apnea. In this study, a cohort of 10,981 patients
was analyzed with 331 deaths and 277 age- and gender-matched controls
for a 10-year period. Multivariate analysis revealed that all-cause mortality
was associated most strongly with COPD (odds ratio [OR] 7.07, 95% CI,
2.75–18.16), with other comorbidities having lower odds ratios (congestive
heart failure, OR 5.47; diabetes mellitus, OR 3.30; BMI increase of 5 kg/m2,
1.44). The mortality associated with OSA is significantly increased with
the presence of COPD.
Evaluation
Testing for sleep apnea is not necessary in all patients who have COPD
[51,52]. Individuals who have COPD who possess typical risk factors for
OSA, such as obesity, chronic snoring, enlarged neck, daytime sleepiness,
and hypertension, should be evaluated according to standard screening
practices. Other individuals who should undergo evaluation include those
who have polycythemia, cor pulmonale, pulmonary hypertension, and neu-
ropsychologic impairments.
Frequently, individuals may first come to clinical attention after initiation
of mechanical ventilation for respiratory exacerbations of COPD. In such
instances, clinical evaluation for the presence of COPD and risks for OSA
are appropriate. Individuals who have known COPD along with obesity,
chronic snoring, and daytime somnolence may warrant empiric treatment
while hospitalized with polysomnography at or soon after hospital discharge
to assess for OSA. The most appropriate method for diagnosis of the over-
lap syndrome continues to be routine polysomnography. Nocturnal oxime-
try, although sufficient for identifying those who have severe desaturations,
is not able to detect those individuals who have more subtle sleep-disordered
breathing with frequent apneas and hypopneas without desaturations less
than 89%, but with significant sleep disruption.
Treatment
Treatment of the overlap syndrome is based on the individual and the se-
verity of the disease. Careful consideration of concomitant medical illnesses,
such as obesity, heart failure, and secondary pulmonary hypertension,
should also be made. Treatment options may include oxygen, oral appliance
therapy, or continuous positive airway pressure (CPAP), and noninvasive
positive pressure ventilation (NIPPV). Auto-titrating CPAP, though com-
monly used in clinical practice, is not currently recommended for individuals
who have COPD, per recommendations from the American Academy of
Sleep Medicine [53].
Patients who have COPD and mild sleep-disordered breathing but signif-
icant nocturnal hypoxemia may be poorly tolerant of CPAP and be best
treated with oxygen and optimum medical management of their COPD.
Because low arterial oxygen may lead to pulmonary hypertension, cor pulmo-
nale, impaired cognitive function, reduced renal blood flow, and polycythe-
mia, studies from the 1980s provide the data supporting supplemental
oxygen in patients who have COPD with respiratory failure [54,55]. In
both of these studies mortality was decreased with increasing number of
hours of daily oxygen use. There are few data to support a survival improve-
ment in patients who do not have daytime hypoxemia or who have isolated
nocturnal hypoxemia. Although there are few data supporting nocturnal
oxygen use in improving pulmonary hemodynamics [56], a stronger body
of evidence demonstrates no significant difference for patients who have
COPD with nocturnal hypoxemia with regard to pulmonary hemodynamics
or mortality [37,57,58]. Because of the theoretic benefit on pulmonary hemo-
dynamics, right heart function, and erythropoietin levels, however, many
practitioners continue to prescribe nocturnal oxygen for patients who have
COPD, mild OSA, or milder forms of the overlap syndrome, especially in
those patients who have these existing complications. Because these oxygen
studies were done before the widespread use of polysomnography, further
evaluation of the benefits of oxygen therapy in those who have COPD and
minimal sleep-disordered breathing, and in those poorly tolerant of CPAP,
is warranted.
In patients who have more severe forms of sleep-disordered breathing,
treatment with CPAP is beneficial for improving the respiratory disturbance
index, nocturnal hypoxemia/hypercapnia, and daytime sleepiness. Cardio-
vascular benefit has been demonstrated in the form of blood pressure reduc-
tion in a few studies [59,60], and fatal and non-fatal cardiovascular events
[61,62]. These studies did not distinguish patients who had COPD as a sep-
arate subgroup, however, so the benefits of treatment with CPAP in the
overlap syndrome are unknown.
Two recent studies assessed the effects of CPAP on lung function. de
Miguel and colleagues [63] assessed 55 patients who had an AHI greater
than or equal to 10 and FEV1 less than 80%. After 6 months of therapy,
statistically significant increases in PaO2, FEV1, and FVC were seen, along
with decreases in PaCO2, serum bicarbonate levels, and alveolar-arterial ox-
ygen difference. No further difference was noted at 18 months of therapy. In
contrast, O’Brien and Whitman [64] reviewed data on 70 patients from their
center and concluded that commonly used markers of lung function
declined in the CPAP-compliant group who had the overlap syndrome;
thus treatment may not alter the course of obstructive airways disease.
For patients who have more severe respiratory insufficiency, NIPPV may
be necessary. There are few published data in the literature on NIPPV in
patients who have the overlap syndrome. One study assessed short-term ther-
apy for patients who had severe OSA-associated hypercapnia and found
benefit [65], but these patients were not specified as having the overlap
syndrome. Subsequent studies on NIPPV have addressed the broader popu-
lation of sleep-disordered breathing associated with hypoventilation (ie, neu-
romuscular disorders, central hypoventilation, and chest wall deformities). A
recent review of NIPPV in severe stable COPD has been published and indi-
cates a subset of individuals on maximal medical regimens may benefit from
treatment with NIPPV through attenuation of compromised respiratory
function and improvement in health-related outcomes [66].
Implications in ICU patients

Patients admitted with the overlap syndrome may not be recognized to
have either disorder on admission. Admission for respiratory exacerbation
of COPD is a common ICU diagnosis, however, and often presents with
respiratory failure and intubation with mechanical ventilation. Patients
who have concomitant obesity, a history of habitual snoring, or hyperten-
sion should be considered at risk for having the overlap syndrome. These
patients are at potentially greater risk for the consequences of sleep disrup-
tion common in ICU patients and should be closely monitored on extuba-
tion. It is likely that untreated OSA may be a factor in recurrent failed
attempts at extubation; consideration of this possibility might reasonably
lead to empiric CPAP or even early tracheotomy in individuals who appear
likely to have OSA and who repeatedly fail weaning and extubation.
Summary
The overlap syndrome is a poorly studied condition of unknown preva-
lence and uncertain outcome. In patients who have advanced-stage COPD,
concomitant OSA likely has significant adverse consequences. The interac-
tion between these two diseases is unclear, however. Further clinical trials
of this entity are urgently needed.
References
[1] Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med 1985;6(4):651–61.
[2] Weitzenblum E, Krieger J, Apprill M, et al. Daytime pulmonary hypertension in patients
with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988;138:345–9.
[3] Bradley TD, Rutherford A, Grossmann RF, et al. Role of daytime hypoxemia in the
pathogenesis of right heart failure in obstructive sleep apnea syndrome. Am Rev Respir
Dis 1985;131:835–9.
[4] Bradley TD, Rutherford A, Lue F, et al. Role of diffuse airway obstruction in the hypercap-
nia of obstructive sleep apnea. Am Rev Respir Dis 1986;134:920–4.
[5] Trask CH, Cree EM. Oximeter studies on patients with chronic obstructive emphysema,
awake and during sleep. N Engl J Med 1962;266:639–42.
[6] Wynne JW, Block AJ, Hemenway J, et al. Disordered breathing and oxygen desatura-
tion during sleep in patients with chronic obstructive lung disease. Am J Med 1979;
66:573–9.
[7] Douglas NJ, Calverley PM, Leggett RJ, et al. Transient hypoxaemia during sleep in chronic
bronchitis and emphysema. Lancet 1979;1:1–4.
[8] Littner MR, McGinty DJ, Arand DL. Determinants of oxygen desaturation in the course of
ventilation during sleep in chronic obstructive pulmonary disease. Am Rev Respir Dis 1980;
122:849–57.
[9] Fleetham J, West P, Mezon B, et al. Sleep, arousals and oxygen desaturation in chronic
obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;
126:429–33.
[10] Calverley PM, Brezinova V, Douglas NJ, et al. The effect of oxygenation on sleep quality in
chronic bronchitis and emphysema. Am Rev Respir Dis 1982;126:206–10.
[11] Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of
COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370(9589):
741–50.
[12] Halbert RJ, Isonaka S, George D, et al. Interpreting COPD prevalence estimates: what is the
true burden of disease? Chest 2003;123:1684–92.
[13] Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-
analysis. Eur Respir J 2006;28(3):523–32.
[14] Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing in middle-
aged adults. N Engl J Med 1993;328:1230–5.
[15] Chin K, Fukuhara S, Takahashi K, et al. Response to shift in perception of sleepiness in
obstructive sleep apnea-hypopnea syndrome before and after treatment with nasal CPAP.
Sleep 2004;27:490–3.
[16] Gottlieb DJ, Whitney CW, Bonekat WH, et al. Relation of sleepiness to respiratory
disturbance index: the sleep heart health study. Arch Intern Med 2002;162:893–900.
[17] Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir
Crit Care Med 2002;165:1217–39.
[18] Guilleminault C, Cumminskey J, Motta J. Chronic obstructive airflow disease and sleep
studies. Am Rev Respir Dis 1980;122:397–406.
[19] Chaouat A, Weitzenblum E, Krieger J, et al. Association of chronic obstructive pulmonary
disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82–6.
[20] Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleep-disordered breathing in
adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med
2003;167:7–14.
[21] Catterall JR, Douglas NJ, Calverley PM, et al. Transient hypoxemia during sleep in chronic
obstructive pulmonary disease is not a sleep apnea syndrome. Am Rev Respir Dis 1983;
128(1):24–9.
[22] Little SA, Elkholy NM, Chalmers GW, et al. Predictors of nocturnal oxygen desaturation in
patients with COPD. Respir Med 1999;93:202–7.
[23] Birchfield RI, Sieker HO, Heyman A. Alterations in respiratory function during natural
sleep. J Lab Clin Med 1959;54:216–22.
[24] Bulow K. Respiration and wakefulness in man. Acta Physiol Scand 1963;59(Suppl 209):
1–110.
[25] Douglas J, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults.
[26] Gleeson K, Zwillich CW, White DP. Chemosensitivity and the ventilatory response to
airflow obstruction during sleep. J Appl Physiol 1989;67:1630–7.
[27] Yamauchi M, Tamaki S, Tomoda K, et al. Evidence for activation of nuclear factor kappaB
in obstructive sleep apnea. Sleep Breath 2006;10:189–93.
[28] Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients
with obstructive sleep apnea. Circulation 2002;105:2462–4.
[29] Can M, Acikgoz S, Mungan G, et al. Serum cardiovascular risk factors in obstructive sleep
apnea. Chest 2006;129:233–7.
[30] Calverley PM, Scott S. Is airway inflammation in chronic obstructive pulmonary disease
(COPD) a risk factor for cardiovascular events? COPD 2006;3:233–42.
[31] Walter RE, Wilk JB, Larson MG, et al. Systemic inflammation and COPD: the Framingham
Heart Study. Chest 2008;133:19–25.
[32] Klink ME, Dodge R, Quan SF. The relation of sleep complaints to respiratory symptoms in
the general population. Chest 1994;104:151–4.
[33] Leitch AG, Clancy LJ, Leggett RJ, et al. Arterial blood gas tensions, hydrogen ion, and
electroencephalogram during sleep in patients with chronic respiratory failure. Thorax
1976;31:730–5.
[34] Valipour A, Lothaller H, Rauscher H, et al. Gender-related differences in symptoms of
patients with suspected breathing disorders in sleep: a clinical population study using the
sleep disorders questionnaire. Sleep 2007;30:312–9.
[35] Boysen PG, Block AJ, Wynn JW, et al. Nocturnal pulmonary hypertension in patients with
chronic obstructive pulmonary disease. Chest 1979;76:536–42.
[36] Fletcher EC, Levin DC. Cardiopulmonary hemodynamics during sleep in subjects with
chronic obstructive pulmonary disease: the effect of short and long-term O2. Chest 1984;
85:6–14.
[37] Chaouat A, Weitzenblum E, Kessler R, et al. Sleep-related O2 desaturation and daytime
pulmonary haemodynamics in COPD patients with mild hypoxaemia. Eur Respir J 1997;
10:1730–5.
[38] Atwood CW, McCrory D, Garcia JG, et al. Pulmonary artery hypertension and sleep-
disordered breathing: ACCP evidence-based clinical practice guidelines. Chest 2004;126:
72S–7S.
[39] Flick MR, Block AJ. Nocturnal vs. diurnal cardiac arrhythmias in patients with chronic
obstructive pulmonary disease. Chest 1979;75:8–11.
[40] Shepard JW, Garrison MW, Grither DA, et al. Relationship of ventricular ectopy to noctur-
nal oxygen desaturation in patients with chronic obstructive pulmonary disease. Am J Med
1985;78:28–34.
[41] Arias MA, Sanchez AM. Obstructive sleep apnea and its relationship to cardiac arrhythmias.
J Cardiovasc Electrophysiol 2007;18:1006–14.
[42] Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of
incident atrial fibrillation. J Am Coll Cardiol 2007;49:565–71.
[43] Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-
disordered breathing: the Sleep Heart Health study. Am J Respir Crit Care Med 2006;173:
910–6.
[44] Mermigkis C, Kopanakis A, Fodvary-Shaefer N, et al. Health-related quality of life in
patients with obstructive sleep apnea and chronic obstructive pulmonary disease (overlap
syndrome). Int J Clin Pract 2007;61:207–11.
[45] Marti S, Gampol G, Munoz X, et al. Mortality in severe sleep apnoea/hypopnoea syndrome
patient: impact of treatment. Eur Respir J 2002;20:1511–8.
[46] He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea.
Experience in 385 male patients. Chest 1988;94:9–14.
[47] Partninen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea
syndrome patients. Mortality. Chest 1988;94:1200–4.
[48] Lavie P, Herer P, Peled R. Mortality in sleep apnea patients: a multivariate analysis of risk
factors. Sleep 1995;18:149–57.
[49] Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease
surveillancedUnited States. 1971–2000. MMWR Surveill Summ 2002;51:1–16.
[50] Lavie P, Herer P, Lavie L. Mortality risk factors in sleep apnoea: a matched case-control
study. J Sleep Res 2007;16:128–34.
[51] Douglas NJ. Are sleep studies necessary in COPD? Lung 1990;168(Suppl):943–7.
[52] Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the manage-
ment of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis
1988;138:341–4.
[53] Littner M, Hishkowitz M, Davila D, et al. Practice parameters for the use of auto-titrating
continuous positive pressure devices for titrating pressure and treating adult patients with
obstructive sleep apnea syndrome. An American Academy of Sleep Medicine report. Sleep
2002;25(2):143–7.
[54] Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in
hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980;93:391–8.
[55] Medical Research Council Working Party Report. Long term domiciliary oxygen therapy in
chronic hypoxic cor pulmonale complicating bronchitis and emphysema. Lancet 1981;
1(8222):681–6.
[56] Fletcher EC, Luckett RA, Goodnight-White S, et al. A double-blind trial of nocturnal
supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary
disease and daytime PaO2 above 60mm Hg. Am Rev Respir Dis 1992;145:1070–6.
[57] Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen
therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999;14(5):1002–8.
[58] Chauouat A, Witzenblum E, Kessler R, et al. Outcome of COPD patients with mild daytime
hypoxaemia with or without sleep-related oxygen desaturation. Eur Respir J 2001;17:
848–55.
[59] Hui DS, To KW, Fok JP, et al. Nasal CPAP reduces systemic blood pressure in patients with
obstructive sleep apnoea and mild sleepiness. Thorax 2006;61:1083–90.
[60] Hla KM, Skatrud JB, Finn L, et al. The effect of correction of sleep-disordered breathing on
BP in untreated hypertension. Chest 2002;122:1125–32.
[61] Marin JM, Carrizo SJ, Ventencte E, et al. Long-term cardiovascular outcomes in men with
obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive
airway pressure: an observational study. Lancet 2005;365:1046–53.
[62] Doherty LS, Kiely JL, Swan V, et al. Long-term effects of nasal continuous positive airway
pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:
2076–84.
[63] de Miguel J, Cabello J, Sanchez-Alarcos JM. Long-term effects of treatment with nasal
continuous positive airway pressure on lung function in patients with overlap syndrome.
Sleep Breath 2002;6:3–10.
[64] O’Brien A, Whitman K. Lack of benefit of continuous positive airway pressure on lung
function in patients with overlap syndrome. Lung 2005;183:389–404.
[65] Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe
obstructive sleep apnea and hypercapnia. Chest 1994;105:434–40.
[66] Kolodziej MA, Jensen L, Rowe B, et al. Systematic review of noninvasive positive pressure
ventilation in severe stable COPD. Eur Respir J 2007;30:293–306.
Crit Care Clin 24 (2008) 565–587
Common Sleep Problems in ICU: Heart

Failure and Sleep-Disordered
Breathing Syndromes
Matthew T. Naughton, MD, FRACP
General Respiratory and Sleep Medicine, Department of Allergy, Immunology
and Respiratory Medicine, and Monash University, The Alfred Hospital,
Melbourne, Victoria 3004, Australia
Heart failure and sleep-disordered breathing are important to the inten-

sivist. Sleep is frequently the ‘‘stress’’ that destabilizes cardiac function and
results in the symptoms that many patients develop that require admission
to ICU. Sleep-related breathing disorders are intertwined with cardiovascu-
lar disease by virtue of their shared real estate (ie, the lungs) and common
interacting cardiopulmonary physiology.
The therapies that have been used to manage long-term obstructive sleep
apnea–hypopnea syndrome (OSAHS) and hypoventilation disorders with
various noninvasive ventilation (NIV) devices (bilevel positive airway pres-
sure [PAP], continuous PAP [CPAP], volume-cycled portable devices) in the
domiciliary setting have been used as the backbone in the development of com-
fortable, portable, and effective NIV devices that are used by intensivists and
emergency physicians to manage acute cardiac and respiratory failure today.
Cardiopulmonary pathophysiology and sleep-disordered breathing

Three pathophysiologic mechanisms characterize sleep-related breathing
disorders, namely: (a) upper airway instability (eg, sleep-related loss of mus-
cle tone leading to snoring and obstructive hypopneas and apneas), (b) re-
spiratory control instability (eg, hyperventilation with circulatory delay
causing periodic drive to breathe) and (c) respiratory pump disorders (eg,
chest wall abnormalities or restrictive ventilatory defects). Each mecha-
nism affects the development of OSAHS (Fig. 1), central sleep apnea
with Cheyne-Stokes respiration (CSA-CSR) (Fig. 2), and sleep-related
E-mail address: m.naughton@alfred.org.au
566 NAUGHTON
Fig. 1. A 5-minute polysomnograph of a patient who has idiopathic cardiomyopathy (LVEF

40%) and OSAHS. Note esophageal pressure swings to 55 mm Hg during apneas associated
with decreases in SpO2 from 95% to 75%, a PtcCO2 ranging between 52 and 57 mm Hg, blood
pressure peak of 170/90 mm Hg and an apnea-hypopnea cycle length of 43 seconds.
hypoventilation (Fig. 3). Each mechanism may be influenced by, or have an

effect on, the cardiovascular system.
Upper airway instability

Upper airway instability and collapse occurs either during inspiration,
when negative intraluminal forces predominate and the so-called ‘‘collaps-
ing pressure’’ is negative, or during expiration, when the intraluminal col-
lapsing pressure is positive [1]. The former usually occurs in patients who
have skeletal or soft tissue anatomic abnormalities (eg, narrow high arched
palate, retrognathia, nasal obstruction), whereas the latter occurs in patients
in whom obesity or drugs affect upper airway tone (sedatives, alcohol [2]).
In either case, upper airway occlusion occurs for periods of 10 to 90 sec-
onds during which time vigorous respiratory drive occurs resulting in nu-
merous futile efforts to inspire. Each effort is associated with increasing
large negative intrathoracic pressure (to as low as 150 cm H2O [3]), while
hypoxia and hypercapnia become progressively greater and the heart rate
slows down (diving reflex) until an arousal occurs (precipitated by hypercap-
nia, hypoxemia, work of breathing), at which time airway patency returns.
Following the apnea, the arousal-related return of airway patency may be
partial (in which snoring persists), or complete (in which ventilation occurs
COMMON SLEEP PROBLEMS IN ICU 567
Fig. 2. A 5-minute polysomnograph of a patient who has advanced ischemic cardiomyopathy

(LVEF 15%) and CSR-CSA. Note absent esophageal pressure swings during the apneas fol-
lowed by swings to 30 mm Hg during the peak of ventilation associated with decreases in
SpO2 from 98% to 94%, PtcCO2 oscillating from 44 to 48 mm Hg, periodic limb movements
in right leg, and an apnea-hyperpnea cycle length of 75 seconds. Also note the cardiac oscilla-
tions on the thermistor trace on apneas 1, 2, half of 3, and 4; these represent an open upper
airway, which closes mid-apnea in the third apnea. Also note some snoring during the peak
of ventilation. Finally, note difference in airflow between oronasal thermistor and nasal pressure
cannulae, indicating intermittent oral airflow, possibly because of nasal obstruction.
without snoring) for the three to five breaths before deep sleep returns. Sys-
temic blood pressure oscillates with each inspiratory effort during the apnea,
then surges up (to as high as 250/150 mm Hg) with the arousal, and later
returns to baseline with the onset of sleep and the next apnea.
Sleep is characterized by a unique autonomic state and this can be dis-
turbed by upper airway instability. If one considers a four-step sleep state
change from (i) quiet wakefulness, to (ii) stages 1 and 2 non–rapid eye move-
ment (REM) sleep, to (iii) stages 3 and 4 non-REM sleep or slow-wave
sleep, and finally to (iv) REM sleep, sympathetic tone decreases from wake-
fulness to stages 1 and 2, and further reduces in slow-wave sleep, then in-
creases in REM sleep to levels seen in wakefulness [4]. Sleep thus has
a powerful effect on sympathetic nervous system (SNS) activity.
Parasympathetic or vagal tone, however, increases with state change from
wakefulness to stages 1 þ 2 and further to slow-wave sleep and REM sleep.
Parasympathetic activity seems to be influenced not just by sleep but also by
circadian timing, such that parasympathetic nervous system (PNS) activity
may be increased during the night in subjects who remain awake [5].
568 NAUGHTON
Fig. 3. A 1-hour polysomnograph of patient on CPAP who during the onset of REM hypoven-
tilates more than 25 minutes with SpO2 drifting from 99% to 70% and PtcCO2 increasing from
45 to 51 mm Hg without any CPAP leak (note constant level of 50 L/min). In contrast to the
patient in Fig. 1, there is persistent hypoxemia with a 6-mm Hg increase in PtcCO2.
Upper airway instability during sleep resulting in snoring, hypopneas, or

apneas results in changes in autonomic control. During the apnea, while air-
flow is absent and hypoxia is occurring, there is an acute reduction in sym-
pathetic activity. When each apnea is terminated, sympathetic activity
surges up, in parallel with increase in heart rate and systemic and pulmonary
artery blood pressure. With recurrent apneas, the overall net sympathetic
activity, as measured awake or asleep, increases [4,6].
Respiratory control instability

Under normal circumstances, respiratory control is influenced by several
factors while awake: cortical factors (to allow respiration to synchronize
with speech, swallowing, laughter, and so forth), a waking neural drive,
and finally a metabolic drive [7].
While asleep, there is loss of cortical control and the waking neural drive.
The metabolic threshold required to stimulate ventilation is increased and
the overall drive to ventilate is diminished by 20%. During sleep ventilation
is under a negative feedback system, wherein metabolic factors (reflecting
the efficiency of ventilation) are sensed centrally by two neurologically dis-
tinct chemoreceptors: a rapidly responsive carotid body and a more slowly
responsive pons. The speed at which messages from the lung are sensed by
the brain is the afferent loop of the feedback system and is usually 10 sec-
onds (time it takes blood leaving the pulmonary vein to reach the peripheral
chemoreceptors). This time can become prolonged in the setting of impaired
cardiac output (slow rate or reduced stroke volume) to values of 20 to 30
seconds [8].
Central and peripheral respiratory control (pons and carotid body, re-
spectively) receive input from the ambient blood gases (pH, Paco2, Pao2),
autonomic control (eg, vagus nerve), and vascular endothelial hormones (ni-
tric oxide, dopamine). Arterial blood gases (mainly Paco2) are sensed rap-
idly by the carotid body, and correlate significantly in the periodicity of
periodic breathing. The Paco2 level is also sensed centrally (pons) in
a more slowly responsive time frame (5 minutes) and correlates significantly
with the background or ambient Paco2 level during sleep [9]. Baroreceptor
input (carotid sinus and aortic arch) also have an effect on respiratory out-
put, such that an increase in blood pressure (or more accurately transmural
pressure) transiently inhibits respiratory drive [10]. Endothelial function
may also alter respiratory control; for example, the development of conges-
tive heart failure (CHF) experimentally in animal models has revealed a loss
of nitric oxide producing endothelium and the development of heightened
ventilatory responses to CO2 [11]. Autonomic changes can also influence re-
spiratory drive: local infusion of norepinephrine results in increased ventila-
tion [12].
Further to CO2 control, pulmonary vagal afferent nerve activity is impor-
tant in determining pulmonary congestion or irritation (eg, alveolitis); stud-
ies have shown that acute increases in pulmonary vascular pressures increase
vagal afferent traffic, which contributes to hyperventilation [13]. Elevated
pulmonary capillary wedge pressure may thus trigger hyperventilation by
way of afferent vagal nerve activity [14]; however, vagally denervated pa-
tients still have hyperventilation and hypocapnia in the setting of heart fail-
ure [15]. Increased vagal afferent activity is thus not necessary for a patient
to develop hyperventilation. Other factors, such as elevated catecholamines
[6,16] and loss of nitric oxide [11] at the chemoreceptor sites, are likely to be
most important in triggering hyperventilation.
The ventilatory response of the brain to the metabolic signal (eg, Paco2) is
usually reduced in normal sleep, but may be increased in conditions of
heightened sympathetic activity. Several studies have now shown a link be-
tween increased ventilatory responsiveness and elevated sympathetic activ-
ity: reduced nitric oxide. The ventilatory response may further increase if
the prevailing Pao2 decreases, which might occur in the setting of ventilation
perfusion (VQ) mismatch secondary to subacute alveolar edema, or a reduc-
tion in pulmonary oxygen stores related to (a) cardiomegaly, (b) obesity, (c)
supine body position, or (d) loss of respiratory accessory muscle activity
during sleep.
Another index of respiratory control instability is loop gain; this is an en-
gineering term that describes the stability of any system under negative
570 NAUGHTON
feedback control and can be described as the ratio of the corrective response
(hyperpnea) to the disturbance (apnea) [1]. A loop gain of greater than 1.0
indicates that for a given disturbance, there is an overcorrection, which is
similar to what is seen with heart failure and central sleep apnea with
Cheyne-Stokes. Factors that can influence loop gain can be a greater venti-
latory response (or a greater overshoot) or mistiming of the ventilatory re-
sponse to a given respiratory pump action.
Respiratory control instability is seen in severe CHF, narcotic use, high
altitude, immature neonates, stroke, some OSAHS patients given CPAP,
and in a further group for whom no cause can be identified (idiopathic cen-
tral sleep apnea) [8]. In common, these patients have an underlying hyper-
ventilation disorder usually awake and asleep, with normal or low Paco2
levels [17–20]. In CHF, Paco2 levels during sleep are lower than wakefulness,
indicating sleep-related factors that increase the drive to ventilate including
(a) increased sympathetic activity, (b) hypoxemia, and (c) further lung-to-
brain circulatory delay with greater overshoot. In all these patient groups,
Paco2 levels are believed to oscillate above and below the apnea threshold
[21] (a physiologic threshold above which CO2 levels stimulate ventilation)
and when Paco2 levels fall below the threshold, ventilation ceases. The in-
crease and decrease in Paco2 levels dictates the pattern of cyclic breathing,
also known as periodic breathing or CSA-CSR. This pattern of respiration
can be identified in stages 1 þ 2 non-REM sleep, is precipitated by an
arousal or state change, has an arousal occurring at the peak of ventilation,
and has relatively normally ventilation during slow-wave (high arousal
threshold) and REM sleep (metabolic and cortical control to ventilate).
In contrast, a second form of respiratory control instability can occur in
which the prevailing Paco2 levels are elevated. Such patients usually have
a permanent pathology centrally (syringomyelia, infarct) or peripheral skel-
etal or myopathic process (eg, kyphoscoliosis, morbid obesity, phrenic nerve
damage). Such patients usually have hypoventilation awake and to a greater
degree while asleep, particularly during REM sleep when the active muscles
of respiration are limited to the diaphragm.
Respiratory pump
Significant lung volume changes occur with changes in posture and sleep/
wake state. These changes are exaggerated in diseases of the nervous, car-
diac, or pulmonary systems, which may result in exaggerated loss of oxygen
stores or greater VQ mismatching.
Under normal conditions, the change in posture from seated to supine re-
sults in a 20% reduction in end-expiratory lung volume [22], and a further
reduction in lung volume occurs with transition from wake to sleep. Respi-
ratory pump muscle activity also alters with sleep with a progressive reduc-
tion in accessory and intercostal muscle activity with sleep and a greater
dependence on diaphragm activity.
The normal VQ matching that we understand is based mainly on upright

physiology wherein there is greater ventilation at the apices and greater per-
fusion in the bases. Normal VQ matching alters with the supine position,
however, predisposing to a slightly greater VQ mismatch. In a rare condi-
tion, the opposite effect occurs, whereby VQ matching improves with supine
position compared with upright position (ie, orthodeoxia), which can occur
in patients who have chronic liver disease presumably related to the devel-
opment of dynamic vascular right-to-left shunts in gravitationally depen-
dent parts of the body.
Reduced pump activity in patients who have cardiovascular disease may
occur in the settings of massive obesity, diaphragmatic palsy post-thoracot-
omy for cardiac surgery, heart failure–related myopathy, effusions, and car-
diomegaly. Reductions in lung volume exaggerate the hypoxemia related to
a disturbance to ventilation, thus exaggerating the plant gain of periodic
breathing.
Congestive heart failure

In addition to arrhythmias, coronary artery disease, and stroke, CHF is
closely linked to sleep-disordered breathing. In recent years, CHF has be-
come the most expensive medical condition in the western world. An in-
creasing prevalence and incidence of CHF, frequent hospitalizations, plus
an increasing variety of medical therapies, many of which are costly (eg,
left ventricular assist devices and biventricular pacers), have contributed
to an annual estimate of $50 billion spent per annum in the United States
on patients who have CHF [23]. The mortality of CHF ranges from 20%
to 50% at 2 years, which equates with many malignancies.
Current understanding of cardiac pathophysiology suggests that CHF is
attributable to either systolic (failure of contraction) or diastolic left ventric-
ular failure (failure of relaxation) or conduction abnormalities (eg, sick sinus
syndrome, atrial fibrillation). It is estimated systolic and diastolic left ven-
tricular dysfunction occurs in up to 6% and 21% of community dwellers
aged 45 years or older, respectively [24].
Patients who have CHF can be staged into four (A–D) categories: stage
A identifies the patient who is at high risk for developing CHF but has no
structural disorder of the heart; stage B refers to a patient who has a struc-
tural disorder of the heart but who has never developed symptoms of CHF;
stage C denotes the patient who has past or current symptoms of CHF as-
sociated with underlying structural heart disease; and stage D designates the
patient who has end-stage disease who requires specialized treatment strat-
egies, such as mechanical circulatory support, continuous inotropic infu-
sions, cardiac transplantation, or hospice care [23].
Treatment strategies have been well defined for CHF because of systolic
or conduction abnormalities, wherein survival has been positively influenced
572 NAUGHTON
by treatment. In contrast, diastolic dysfunction remains unknown territory

in terms of cause and optimal management.
OSAHS is likely to be an important cause of diastolic dysfunction (Box 1)
because of hypoxemia [25], tachycardia [26], elevated left ventricular trans-
mural pressure (TMP) (Fig. 4), and vascular injury, which left unrecognized
may lead to systolic dysfunction and conduction abnormalities. According
to Laplace’s law, the left ventricular afterload is a product of TMP with ra-
dius and divided by wall thickness. Conditions that elevate TMP are detri-
mental to the failing heart, whereas treatments that reduce TMP are
beneficial.
CSA-CSR may be a secondary response to severe CHF (of any cause) at-
tributable to hyperventilation, circulatory delay, and plant gain (wet lungs)
(Fig. 5). An overlap of CSA-CSR and OSAHS is common within nights [20]
and frequently the same patient oscillates from one to another depending on
CHF status.
Under normal conditions, cardiac output decreases during normal sleep,
by approximately 20%, by the mechanisms of a decrease in heart rate and
stroke volume. With upper airway instability and the development of
OSAHS cardiac output may decrease further for several reasons (see Box 1).
First, the left ventricular transmural pressure increases (because of large
negative intrathoracic pressures during the apnea and elevated systolic pres-
sures during the arousal). Elevated transmural pressure (akin to elevated
afterload) impedes stroke volume mildly in healthy individuals, and to
a greater degree in patients who have impaired baseline cardiac contractility.
Box 1. Mechanisms responsible for obstructive sleep

apnea–hypopnea syndrome contributing to vascular disease
Hypoxemia and hypercapnia
Increased sympathetic activity and respiratory drive
Negative intrathoracic pressure
Increased left ventricular afterload
Increased venous return
Endothelial damage attributable to hypoxia/hyperoxia
Loss of nitric oxide production
Arousal
Sympathetic activation
Increased heart rate
Systemic hypertension
Pulmonary hypertension
Patent foramen ovale
Shunting right to left
Stroke
Profound hypoxemia
Fig. 4. A single-chamber ventricle, aorta, and thoracic box connected to external atmosphere
by the throat. Left ventricular transmural pressure (TMP) is then illustrated during systole at
peak inspiration under circumstances of normal ventilation (125 mm Hg) (A), OSASH (280
mm Hg) (B), CSA-CSR (150 mm Hg) (C), acute cardiogenic pulmonary edema (APE) (230
mm Hg) (D), and CPAP (125 mm Hg) (E). TMP represents the difference in pressures between
intracardiac and intrathoracic pressures. Note the elevated TMP in OSAHS and CSA-CSR and
APO compared with normal, and the large reduction in TMP with a small amount of CPAP.
Note the increase in end-expiratory lung volume (cross-hatched area) with CPAP.
Second, inspiratory efforts raise intrathoracic blood volume and right

ventricular dilatation may occur, shifting the intraventricular septum to-
ward the left ventricle.
Third, stroke volume may decrease with obstructive sleep-disordered breath-
ing due directly to hypoxia (during the apnea) and tachycardia (at arousal),
which have the capacity to precipitate impaired cardiac relaxation, thus reduced
filling during diastole and the development of diastolic dysfunction.
Fourth, structural changes to the low pressure left atrium attributable to
the large negative intrathoracic pressure and impaired relaxation may lead
574 NAUGHTON
Fig. 5. (A) Summary of the control of ventilation with both a vagal afferent feedback and ar-
terial blood Paco2 feedback (which depends on cardiac output and circulatory delay, 10 seconds
in normals) which drives ventilation. (B) In the CSA-CSR diagram, the ventilatory responses
are heightened (peripheral and central illustrated with larger yellow and brown boxes, respec-
tively) and a longer circulatory delay and a relatively larger font heart and smaller font lungs
consistent with relative restrictive ventilatory defect with a greater respiratory drive. (C) The
last figure illustrates the effect upper airway instability (snoring or apneas) might have on reduc-
ing airflow.
to left atrial dilatation and then to atrial fibrillation, which further reduces
cardiac output.
Fifth, with venous engorgement of the pulmonary vascular tree, alveolar
leak may occur leading in extreme situations to the development of pulmo-
nary edema.
Finally, elevations of right-sided pressures may lead to transient opening

of the foramen ovale [27]; however, patent foramen ovale is said to be pres-
ent (although latent) in as much as 25% of the population.
There is now experimental and clinical evidence to support the hypothesis
that OSAHS is deleterious to cardiac function. First, studies in dogs have
shown that 1 to 3 months of repetitive apneas can lead to impaired left ven-
tricular ejection function (LVEF) and hypertension [28]. OSAHS is also
strongly associated with systolic heart failure in human studies [29]. In the
Sleep Heart Health Study [30] the largest cardiovascular risk from OSAHS
was seen for a history of cardiac failure. Those who had an apnea-hypopnea
index [AHI] greater than 11 events per hour had a relative risk of 2.4 for re-
porting a history of CHF compared with those who had an AHI less than
1.4 events per hour.
Obstructive sleep apnea–hypopnea syndrome and diastolic heart failure

The apnea-induced hemodynamic changes cause acute reductions in left
ventricular (LV) diastolic function. Negative intrathoracic pressure causes
increased right ventricular filling with a subsequent shift of the intraventric-
ular septum into the LV cavity. This negative pressure reduces LV diastolic
compliance. Hypoxemia leads to delays in ventricular relaxation and tachy-
cardia [25,26], both of which also impair diastolic function.
Chronically, OSAHS is associated with hypertension and increased LV
wall thickness, which may lead to LV diastolic dysfunction [28,31]. It re-
mains controversial, however, whether the change in LV muscle bulk occurs
independently of associated hypertension, because evidence to this point in
time has been conflicting.
Recently [31], a report described reversible LV diastolic dysfunction in
a group of patients who had OSAHS using a randomized controlled
cross-over design. Patients who have diastolic dysfunction do not seem to
have predisposition to hyperventilation or hypocapnia and thus do not de-
velop CSA-CSR [32].
Obstructive sleep apnea–hypopnea syndrome and systolic heart failure

If OSAHS adversely affects LVEF then one would expect improvement
in cardiac performance following its treatment. Strong evidence supporting
a beneficial effect of CPAP has now begun to emerge. A recent randomized
controlled trial has shown improvements in LVEF from 25% to 34% with
1-month CPAP treatment of OSAHS in patients (n ¼ 24) who had systolic
heart failure in addition to reductions in chamber size [33]. In a larger (n ¼
40) and longer (3 months) randomized controlled Australian study, LVEF
increased from 38% to 43% with CPAP in addition to significant improve-
ments in quality of life and autonomic activity (Table 1) [34].
576
Table 1
Outcomes of long-term continuous positive airway pressure in congestive heart failure and obstructive sleep apnea
Author Comparison Na Time (months) DLVEF Other
Diastolic
Arias, et al [31] RCX-over 26 3 na [LV diastolic dysfunction:
(E/A, deceleration and isovolemic
relaxation time
Systolic
NAUGHTON
Krieger, et al [90] BþA 29 12 59/63
Malone, et al [91] BþA 8 1 37/49
Alchanatis, et al [92] BþA 18/29 6 53/56
Laaban, et al [93] BþA 13/169 12 44/62
Kaneko, et al [33] RCT 24/138 1 27/36 YLV dimensions and BP
Mansfield, et al [34] RCT 55/156 3 38/43 [QOL, YSNA
Artz, et al [94] RCT-Oxygen 22 3 31/36
Abbreviations: B þ A, before-and-after trial design; BP, systemic blood pressure; E/A, early/atrial contraction; LV, left ventricular; LVEF, left ventricular
ejection fraction; QOL, quality of life; RCT, randomized controlled trial; RCX-over, randomized controlled cross-over trial; SNA, sympathetic nervous
system.
a
Number studied/number screened.
Central sleep apnea with Cheyne-Stokes respiration

CSA-CSR is seen in 30% of patients who have systolic heart failure and
has features that may assist differentiating it from OSAHS (Table 2). Symp-
toms of CSA-CSR overlap with the symptoms of moderate to severe CHF.
It is characterized by a crescendo-decrescendo breathing pattern, usually
precipitated by sleep onset, state change, or an arousal that occurs mainly
during stages 1 and 2 non-REM sleep. Occasionally it has been noted during
wakefulness [35,36], and rarely is it seen in REM sleep. Ancillary features are
hypocapnia [17], elevated levels of sympathetic activity in the urine [6,16]
and directly in the heart [35], elevated pulmonary capillary wedge pressures
[14,19], dilated cardiac chamber size, elevated central and peripheral chemo-
sensitivity, and greater frequency of atrial [29] and ventricular arrhythmias
[37,38]. It usually occurs in men, and far less frequently in postmenopausal
women. Increased mortality with CSA-CSR compared with normal breath-
ing [39] has been suggested but not confirmed in all studies [40].
The pathogenesis of CSA-CSR relates to a disturbance of respiratory
control (see Fig. 5). It is believed that the primary abnormality is hyperven-
tilation that causes hypocapnia, such that the arterial CO2 level is less than
that required to stimulate ventilation (apnea threshold), which results in
a central apnea. Increased ventilatory responses have been noted at rest
[9] and during exercise [41]. While apneic, the Paco2 level increases until it
crosses the apneic threshold, following which ventilation resumes, but at
a hyperpneic rate, which drives the Paco2 level down below the apneic
threshold once again. The apnea–hyperpnea cycle length is characteristically
greater than 45 seconds (mean 60 seconds), which assists in distinguishing it
from idiopathic central sleep apnea in which cardiac function is normal. The
cycle length also correlates with the degree of cardiac impairment (eg,
LVEF) [8,42].
CSA-CSR is associated with more severe CHF, but does not necessarily
cause worsening of CHF. Indeed there may be theoretic benefits with
Table 2
Clinical features that assist distinguishing obstructive sleep apnea–hypopnea syndrome from
central sleep apnea with Cheyne-Stokes respiration
OSAHS CSA-CSR
Gender Male þ female Male
Age Younger Older
Snoring history Yes Occasionally
Atrial fibrillation Occasionally More frequent
Obesity Yes Less common
Carbon dioxide Normal/high Low/normal
CHF severity Mild-moderate Moderate-severe
Hypoxemia Moderate Mild
Intrathoracic swings Large Mild
Sleep stage REM Stage 1 þ 2
578 NAUGHTON
CSA-CSR, such that it is a response to a failing heart. Several lines of evi-

dence are in support. First, the hyperventilation phase of CSA-CSR is asso-
ciated with an increase in end-expiratory lung volume [43], which would
assist in overcoming the restrictive ventilatory defect associated with severe
CHF. Second, stroke volume appears to increase during the hyperventilation
period [44] possibly because of the additional respiratory pump assisting the
cardiac pump. Third, hyperventilation and resultant alkalosis (and thus
avoidance of acidosis) has been shown to be advantageous to cardiac muscle
in reduced preparations [45]. Fourth, intermittent hyperventilation followed
by rest (ie, central apnea), from a biomedical engineering point of view, al-
lows a greater work efficiency [46]. Finally, the large inspiratory efforts of
CSA-CSR attenuate the sympathetic activity [47].
Treatment of CSA-CSR in the setting of CHF depends on the cause of
CHF (Box 2). If the cause is rate related (eg, sick sinus syndrome), then
correction of rhythm is crucial (ie, remove negative chronotropic drugs,
consider pacemaker). In the setting of a widened QRS complex on the car-
diograph, and LVEF less than 35%, consideration should be made for car-
diac resynchronization therapy (CRT). Two recent articles have shown
improvements in CSA-CSR with CRT, the first in 14 patients [48] and
the second in 12 patients [49], in which the AHI decreased from 19 to 5
and 31 to 15 events per hour, respectively. Of note, however, was that
the improvement in CSA-CSR was not universal (40% got worse) [49]
and patients remained relatively hypoxemic (minimum oxyhemoglobin sat-
uration [SpO2] 83% to 87% [48]).
Box 2. Management of heart failure in central sleep apnea

with Cheyne-Stokes respiration
Pump related (LVEF<35%)
Optimize medical treatments (ACE inhibitor,
consider beta-blockers)
Continuous positive airway pressure
Adaptive pressure support servo-ventilation
Supplemental oxygen to achieve SpO2 95%
Cardiac transplantation
Rate related (mean sleep heart rate <45 bpm or LBBB)
Cease negative inotropic drugs
Exclude hypothyroids
Consider pacemaker (demand if heart block or biventricular
if LBBB)
Abbreviations: ACE, angiotensin-converting enzyme; LBBB, left bundle branch

block.
If the cause of CSA-CSR is left ventricular pump failure, then medical

treatment to reduce afterload (eg, angiotensin-converting enzyme inhibitors)
and preload (diuretics) is needed. Acetazolamide has been used for its meta-
bolic acidosis side effect [50] in a before-and-after study without improvement
in cardiac outcomes reported. A further randomized controlled trial of acet-
azolamide for 6 days supported its role in abolishing CSA-CSR; however,
there was no effect on cardiac function [51]. Theophylline has also been
used for CSA-CSR successfully; however, arrhythmic side effects and lack
of cardiac data would preclude its use to experimentation only [52]. Following
this, if CSA-CSR persists, then consideration should be given to PAP.
PAP, given at a continuous level (5–20 cm H2O) by way of a face mask, is
the first-line treatment of acute cardiogenic pulmonary edema, where level 1
evidence-based medicine has been reached (Box 3, Table 3). Bilevel PAP has
not been shown to be superior in such patients, and is restricted unless mod-
erate to severe hypercapnia persists.
In patients who have chronic pulmonary edema (ie, CSA-CSR) CPAP
has also been observed to assist cardiac function and secondarily reduce
CSA-CSR. CPAP exerts its beneficial effects by increasing lung volume, re-
ducing the left ventricular transmural pressure [53], assisting inspiratory
muscles [54], and increasing alveolar pressure, thereby reducing alveolar
edema (Table 4). Reduced cardiac oxygen consumption [55] and sympa-
thetic drive [56] and greater heart rate variability [57] have been reported
with acute application of CPAP in patients who have CHF. CPAP is gener-
ally used chronically at night during sleep, when it has additional advan-
tages of maintaining upper airway patency, which can be embarrassed
because of upper airway edema or pre-existing OSA.
Three-month randomized controlled trials of nocturnal CPAP in patients
who have CHF with CSA-CSR (Table 5) have shown improved LVEF [58],
reduced sympathetic activity [16] and ANP levels [59], reduced left ventric-
ular chamber dimensions and associated mitral regurgitation [59], reduced
Box 3. Mechanisms of positive airway pressure in heart failure

Upper airway stability
Intrathoracic
Increase end-expiratory lung volume
Increase alveolar pressure
Assist inspiratory muscles
Reduce left ventricular transmural pressure
Reduce preload
Reduce cardiac chamber size
Reduce cardiac mechanical work
Increase dead space and thereby increase CO2
Attenuate sympathetic activity
580 NAUGHTON
Table 3
Outcomes of continuous positive airway pressure in acute pulmonary edema
Poulton [75] BþA 22 patients who have CHF (2 with CSA-CSR)
improve clinically with CPAP
Barach, et al [76] BþA 16 patients who have CHF improve with CPAP
Grace and Greenbaum [77] BþA 21 patients who have CHF have improved CO
with 3–8 cm H2O CPAP when PCWPO12 mm Hg
Rasanen, et al [78] BþA 65% of patients who have CHF have better ABG
with 10 cm H2O CPAP for 10–180 min
Bersten, et al [79] RCT [ABG, RR, HR, Yintubation rate with
CPAP 10 24 h
Baratz, et al [80] BþA 16% [CO in 7/13 patients who have APE,
PCWPO20 mm Hg with 5–15 cm H2O
CPAP over 20–60 min
Abbreviations: ABG, arterial blood gases; APE, acute cardiogenic pulmonary edema; B þ A,
before-and-after trial design; CO, cardiac output; HR, heart rate; PCWP, pulmonary capillary
wedge pressure; RCT, randomized controlled trial; RR, respiratory rate.
minute volume of ventilation and increasing Paco2 levels [60], and reduced
hospital admissions in a single-center study, and a tendency to improved
transplant-free survival [39].
A longer-term Canadian study over 11 sites with 408 patients who had
LVEF less than 40% and AHI greater than 15 events per hour attributable
mainly to CSA-CSR were randomized for 2 years to continued optimal
medical management or the addition of CPAP [61]. The study failed to
show an improvement with CPAP (mean 9 cm H2O and 5 hours adherence
per night) in transplant-free survival; however, there were significant im-
provements noted in AHI, nocturnal SpO2, LVEF, and plasma norepineph-
rine. A subgroup on CPAP in whom the AHI fell to less than 15 events per
Table 4
Outcomes of acute continuous positive airway pressure in stable congestive heart failure
Bradley, et al [81] 22% [SV with 5 cm H2O 10 min
with PCWPO12 mm Hg. No D control
and PCWP!12 gps
DeHoyas, et al [82] Dose effect of 0, 5, 10 cm H2O CPAP on SV
in CHF with PCWPO12 mm Hg
Liston, et al [83] 20% YSV with 5 cm H2O 3 h in 7 patients
who had mean PCWP 21 mm Hg
Kiely, et al [84] 10 cm H2O CPAP 30 min induced YCI
(1.99 to 1.76 L/min/m2) in CHF patients
who had AF
Kaye, et al [55,56] Reduced myocardial SNA and O2 consumption
with CPAP 10 10 min
Butler, et al [57] YSNA and [vagal markers of heart rate variability
with 10 cm H2O 45 min
Naughton, et al [53,85,86] YCardiac and respiratory work, [lung volumes
0, 5, 7.5, 10 cm H2O min each
Abbreviations: AF, atrial fibrillation; CI, cardiac index; PCWP, pulmonary capillary wedge
pressure; SV, stroke volume; SNA, sympathetic nervous system activity.
Table 5
Outcomes of long-term continuous positive airway pressure on left ventricular ejection fraction in congestive heart failure and central sleep apnea with
Cheyne-Stokes respiration
COMMON SLEEP PROBLEMS IN ICU

Author Trial N Duration CPAP T DLVEF Other
Takasaki, et al [87] BþA 5 1 mo 8–12.5 NS 31/38 YAHI (60/9)
Buckle, et al [88] BþA 8 1 night 5–7.5 NS 24/NS No D arousals, AHI, MSLT
Davies, et al [89] BþA 8 2 wk 7.5 NS 17/13 Incomplete data
Naughton, et al [58] RCT 24 3 mo 10 5.9 20/28 YV, SNA, AHI (43/15), [CO2
Tkacova, et al [59] RCT 17 3 mo 10 5.5 20/28 YMRF, ANP
Sinn, et al [39] RCT 29 5 y 10 5.6 21/29 [Survival with CPAP (72% versus 45% at 36 mo)
Bradley, et al [61] RCT 258 2 y 8.5 4 25/27 YSNA, AHI (40/19), [6MWD, no D survival
Artz, et al [62] RCT 210 2 y 9 4.6 26/29 57% CSR-CSA suppressed with CPAP
[ Survival if CSR-CSA suppressed (91% versus 76% versus 70%)
Abbreviations: AHI, apnea-hypopnea index; ANP, atrial natriuretic peptide; B þ A, before-and-after trial; CPAP T, CPAP pressure (cm H2O) and
nightly time used (h); LVEF, left ventricular ejection fraction; MRF, mitral regurgitant fraction; MSLT, multiple sleep latency test; NS, not stated;
RCT, randomized controlled trial; SNA, sympathetic nervous system activity; V, minute ventilation; 6MWD, 6 minute walk distance.
581
582 NAUGHTON
hour at 3 months (AHI from 34 to 6 events per hour) experienced a signifi-

cant improvement in survival compared with the control group and those
patients who did not experience a decrease in AHI on CPAP [62].
Treatments other than CPAP have been used for CSA-CSR. PAP deliv-
ered by adaptive pressure support servo-ventilation (APSSV) has been shown
to have a benefit in sleep quality and an increase in oxygen saturation, and an
increase in transcutaneous Pco2 (PtcCO2) [63]. Although strictly a positive
pressure ventilator, APSSV causes an increase in CO2, assumed to be attrib-
utable to a decrease in minute volume of ventilation, secondary to greater
amounts of slow-wave and REM sleep (when ventilation is reduced) and re-
duced arousal frequency. Two before-and-after studies have supported the
long-term use of APSSV [64,65] in terms of severity of CSA-CSR and cardiac
function. A single randomized controlled trial of APSSV versus sham CPAP
[66] indicated a beneficial decrease in sleepiness (Osler value increased 9 min-
utes) and better indirect markers of CHF control (ie, a decrease in brain
natriuretic peptide and lower 24-hour urinary adrenaline) with APSSV but
unfortunately no significant difference in quality of life or echocardiography.
Oxygen therapy has been used widely to treat CSA-CSR in the setting of
CHF, in which AHI has been reported to decrease by 50% [67,68] but often
inspired oxygen concentrations up to 50% were required. Unfortunately,
however, improvements in objective measures of cardiac function have
not been forthcoming. Moreover, studies of acute oxygen exposure to pa-
tients who have CHF indicate a detrimental effect of oxygen on cardiac out-
put [69,70]. Proposed mechanisms include vascular damage because of the
development of oxygen radicals or attenuation of the cardiac efferent signals
from the chemoreceptors [70]. Oxygen, especially high-flow, should thus be
used with caution in patients who have CHF.
Supplemental CO2 [71] and dead space [72] similarly elevate arterial Pco2
levels, to a level that sits consistently above the apnea threshold. As such,
the periodicity of hyperventilation then apnea is replaced by continuous hy-
perventilation, and, as with theophylline [52], sleep quality does not improve
[73]. Outcomes related to CHF have also been lacking, and as such this form of
treatment should remain in the realm of the experimental rather than the
therapeutic.
Cardiac transplantation has been shown to be effective in improving
CSA-CSR [74]; however, in a small subgroup, CSA-CSR continues but at
a much lower frequency. Also, some patients may convert to OSAHS, which
may represent upper airway instability directly due to the transplantation
(eg, steroid), or unearthing a pre-existing OSAHS.
References
[1] Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in ob-
structive sleep apnea. Am J Respir Crit Care Med 2004;170:1225–32.
[2] Scanlan MF, Roebuck T, Little PJ, et al. Effect of moderate alcohol upon sleep, breathing
and sympathetic activity. Eur Respir J 2000;16:909–13.
[3] Suzuki M, Ogawa H, Okabe S, et al. Digital recording and analysis of esophageal pres-
sure for patients with obstructive sleep apnea–hypopnea syndrome. Sleep Breath 2005;9:
64–72.
[4] Somers VK, Dyken ME, Clary MP, et al. Sympathetic activity neural mechanisms in ob-
structive sleep apnea. J Clin Invest 1995;96:1897–904.
[5] Burgess HJ, Trinder J, Kim Y, et al. Sleep and circadian influences on cardiac autonomic ner-
vous system activity. Am J Physiol Heart Circ Physiol 1997;273:H1761–8.
[6] Solin P, Kaye DM, Little PH, et al. Impact of sleep apnea on sympathetic nervous system
activity in heart failure. Chest 2003;123:1119–26.
[7] Dempsey JA, Smith CA, Prybylowski T, et al. The ventilatory responsiveness to CO2 below
eupnoea as a determinant of ventilatory stability in sleep. J Physiol 2004;560:1–11.
[8] Solin P, Roebuck T, Swieca J, et al. Effects of cardiac dysfunction upon non-hypercapnic
central sleep apnea. Chest 1998;113:104–10.
[9] Solin P, Roebuck T, Johns DP, et al. Peripheral and central ventilatory responses in
central sleep apnea with and without heart failure. Am J Respir Crit Care Med 2000;162:
2194–200.
[10] Carlson JT, Hedner JA, Sellgren J, et al. Depressed baroreflex sensitivity in patients with ob-
structive sleep apnea. Am J Respir Crit Care Med 1996;154:1490–6.
[11] Sun SY, Wang W, Zucker IH, et al. Enhanced peripheral chemoreceptor function in con-
scious rabbits with pacing induced heart failure. J Appl Physiol 1999;86:1264–72.
[12] Heistad DD, Wheeler RC, Mark AL, et al. Effects of adrenergic stimulation on ventilation in
man. J Clin Invest 1972;51:1469–75.
[13] Churchill ER, Cope O. The rapid and shallow breathing resulting from pulmonary conges-
tion and edema. J Exp Med 1929;49:531–7.
[14] Solin P, Bergin P, Richardson M, et al. Influence of pulmonary capillary wedge pressure on
central apnea in heart failure. Circulation 1999;99:1574–9.
[15] Solin P, Snell GI, Williams TJ, et al. Central sleep apnoea in congestive heart failure despite
vagal denervation after bilateral lung transplantation. Eur Respir J 1998;12:495–8.
[16] Naughton MT, Benard DC, Liu PP, et al. Effects of nasal CPAP on sympathetic activity in
patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995;152:
473–9.
[17] Naughton MT, Benard D, Tam A, et al. Role of hyperventilation in the pathogenesis of cen-
tral sleep apneas in patients with congestive heart failure. Am Rev Respir Dis 1993;148:
330–8.
[18] Nopmaneejumruslers C, Kaneko Y, Hajek V, et al. Cheyne-Stokes respiration in stroke. Re-
lationship to hypocapnia and occult cardiac dysfunction. Am J Respir Crit Care Med 2005;
171:1048–52.
[19] Lorenzi-Filho G, Azevedo ER, Parker JD, et al. Relationship of carbon dioxide tension
in arterial blood to pulmonary wedge pressure in heart failure. Eur Respir J 2002;19:
37–40.
[20] Tkacova R, Niroumand M, Lorenzi-Filho G, et al. Overnight shift from obstructive to cen-
tral apneas in patients with heart failure: role of PCO2 and circulatory delay. Circulation
2001;103:238–43.
[21] Xie A, Skatrud JB, Puleo DS, et al. Apnea-hypopnea threshold for CO2 in patients with con-
gestive heart failure. Am J Respir Crit Care Med 2002;165:1245–50.
[22] Yap JCH, Moore DM, Cleland JG, et al. Effect of supine posture on respiratory mechanics
in chronic left ventricular failure. Am J Respir Crit Care Med 2000;162:1285–91.
[23] Hunt SA, Baker DW, Marshall H, et al. Guidelines for the valuation and management of
chronic heart failure in the adult: executive summary. Circulation 2001;104:2996–3007.
[24] Redfield MM, Jacobsen SJ, Burnatt JC, et al. Burden of systolic and diastolic ventricular
dysfunction in the community. JAMA 2003;289:194–202.
584 NAUGHTON
[25] Cargill RI, Kiely DG, Lipworth BJ. Adverse effects of hypoxaemia on diastolic filling in hu-
mans. Clin Sci (Lond) 1995;89:165–9.
[26] Serizawa T, Vogel WM, Apstein CS, et al. Comparison of acute alterations in left ventricular
relaxation and diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocar-
dial oxygen supply-demand imbalance. J Clin Invest 1981;68:91–102.
[27] Shanoudy H, Soliman A, Raggi P, et al. Prevalence of patent foramen ovale and its contri-
bution to hypoxemia in patients with obstructive sleep apnea. Chest 1998;113:91–6.
[28] Parker JD, Brooks D, Kozar LF, et al. Acute and chronic effects of airway obstruction on
canine left ventricular performance. Am J Respir Crit Care Med 1999;160:1888–96.
[29] Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in
450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:
1101–6.
[30] Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular dis-
ease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med
2001;163:19–25.
[31] Arias MA, Garcia-Rio F, Alonso-Fernandez A, et al. Obstructive sleep apnea syndrome af-
fects left ventricular diastolic function. Effects of nasal continuous positive airway pressure
in men. Circulation 2005;112:375–83.
[32] Solin P, Roebuck T, Naughton MT. Cardiac diastolic function and hypercapnic ventilatory
responses in central sleep apnoea. Eur Respir J 2002;20:717–23.
[33] Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway
pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;
348:1233–41.
[34] Mansfield DR, Gollogly NC, Richardson M, et al. Randomized trial of continuous positive
airway treatment of obstructive sleep apnea in heart failure. Am J Respir Crit Care Med
2004;169:1–6.
[35] Mansfield DR, Kaye DM, Hans Brunner P, et al. Raised sympathetic nerve activity in heart
failure and central sleep apnea is due to heart failure severity. Circulation 2003;107:
1396–400.
[36] Poinkowski P, Anker SD, Chua TP, et al. Oscillatory breathing patterns during wakefulness
in patients with chronic heart failure. Clinical implications and role of augmented peripheral
chemosensitivity. Circulation 1999;100:2418–24.
[37] Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular
irritability in patients with heart failure. Circulation 2000;101:392–7.
[38] Lanfranchie PA, Somers VK, Braghiroli A, et al. Central sleep apnea in left ventricular dys-
function. Prevalence and implications for arrhythmic risk. Circulation 2003;107:727–32.
[39] Sin DD, Logan AG, Fitzgerald FS, et al. Effcets of continuous positive airway pressure on
cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respira-
tion. Circulation 2000;102:61–6.
[40] Roebuck T, Solin P, Kaye DM, et al. Increased long term mortality due to sleep apnea in
heart failure is yet to be proven. Eur Respir J 2004;23:735–40.
[41] Artz M, Harth M, Luchner A, et al. Enhanced ventilatory response to exercise in patients
with chronic heart failure and central sleep apnea. Circulation 2003;107:1998–2003.
[42] Hall M, Xie A, Rutherford R, et al. Cycle length of periodic breathing in patients with and
without heart failure. Am J Respir Crit Care Med 1996;154:376–81.
[43] Brack T, Juban A, Laghi F, et al. Fluctuations in end-expiratory lung volume during
Cheyne-Stokes respiration. Am J Respir Crit Care Med 2005;171:1408–13.
[44] Maze SS, Kotler MN, Parry WR. Doppler evaluation of changing cardiac dynamics during
Cheyne-Stokes respiration. Chest 1989;95:525–9.
[45] Bing OH, Brooks WW, Messer JV. Heart muscle viability following hypoxia: protective
effects of acidosis. Science 1973;180:1297–8.
[46] Levine M, Cleave JP, Dodds C. Can periodic breathing have advantages for oxygenation?
J Theor Biol 1995;172:355–68.
[47] Naughton MT. Controversies in sleep medicine. Is Cheyne-Stokes detrimental in patients

with congestive heart failure? Sleep Breath 2000;4:127–8.
[48] Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac resynchronization therapy improves
central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure.
J Am Coll Cardiol 2004;44:68–71.
[49] Gabor JY, Newman DA, Barnard-Roberts V, et al. Improvement in Cheyne-Stokes respira-
tion following cardiac resynchronization therapy. Eur Respir J 2005;26:95–100.
[50] DeBacker WA, Verbraecken J, Willemen M, et al. Central apnea index decreases after pro-
longed treatment with acetazolamide. Am J Respir Crit Care Med 1995;151:87–91.
[51] Javaheri S. Acetazolamide improves central sleep apnea in heart failure. A double blind pro-
spective trial. Am J Respir Crit Care Med 2006;173:234–7.
[52] Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep disordered breathing in
heart failure. N Engl J Med 1996;335:562–7.
[53] Naughton MT, Rahman MA, Hara K, et al. Cardio-thoracic effects of continuous positive
airway pressure in patients with heart failure. Circulation 1995;91:1725–31.
[54] Granton JT, Naughton MT, Benard DC, et al. Continuous positive airway pressure im-
proves inspiratory muscle strength in patients with heart failure and Cheyne-Stokes respira-
tion during sleep. Am J Respir Crit Care Med 1996;153:277–82.
[55] Kaye DM, Mansfield D, Naughton MT. Continuous positive airway pressure reduces myo-
cardial oxygen consumption in congestive heart failure. Clin Sci (Lond) 2004;106:599–603.
[56] Kaye DM, Mansfield D, Aggarwal A, et al. Acute effects of continuous positive airway pres-
sure on cardiac sympathetic tone in congestive heart failure. Circulation 2001;103:2336–8.
[57] Butler GC, Naughton MT, Rahman MA, et al. Continuous positive airway pressure in-
creases heart rate variability in congestive heart failure. J Am Coll Cardiol 1995;25:672–9.
[58] Naughton MT, Liu PP, Benard DC, et al. Treatment of congestive heart failure and Cheyne-
Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit
Care Med 1995;151:92–7.
[59] Tkacova R, Liu PP, Naughton MT, et al. Effect of continuous positive airway pressure on
mitral regurgitation and atrial natriuretic peptide in patients with heart failure and central
sleep apnea. J Am Coll Cardiol 1997;30:739–45.
[60] Naughton MT, Benard DC, Rutherford R, et al. Effect of continuous positive airway pres-
sure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care Med
1994;150:1598–604.
[61] Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central
sleep apnea and heart failure. N Engl J Med 2005;353:2025–33.
[62] Artz M, Floras JS, Logan AG, et al. Suppression of central sleep apnoea by continuous pos-
itive airway pressure and transplant-free survival in heart failure. A post hoc analysis of the
Canadian Continuous Positive Airway Pressure for Patients with central sleep apnoea and
heart failure trial (CANPAP). Circulation 2007;115:3173–80.
[63] Teschler H, Dohring J, Wang YM, et al. Adaptive pressure support servo-ventilation: a novel
treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;
164:614–9.
[64] Kasai T, Narui K, Dohi T, et al. First experience of using new adaptive servo-ventilation de-
vice for Cheyne-Stokes respiration with central sleep apnea among Japanese patients with
congestive heart failure: report of 4 clinical cases. Circ J 2006;70:1148–54.
[65] Topfer V, El-Sebai M, Wessendorf TE, et al. Adaptive servoventilation: effect on Cheyne-
Stokes respiration and quality of life. Pneumologie 2004;58:28–32.
[66] Pepperell JC, Maskell NA, Jones DR, et al. A randomized controlled trial of adaptive ven-
tilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 2003;168:
1109–14.
[67] Andreas S, Clemens C, Sandholzer H, et al. Improvement of exercise capacity with treatment
of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol
1996;27:1486–90.
586 NAUGHTON
[68] Franklin KA, Eriksson P, Sahlin C, et al. Reversal of central sleep apnea with oxygen. Chest
1997;111:163–9.
[69] Haque WA, Beohmer J, Clemson BS, et al. Hemodynamic effects of supplemental oxygen
administration in congestive heart failure. J Am Coll Cardiol 1996;27:353–7.
[70] Mak S, Azevedo ER, Liu PP, et al. Effect of hyperoxia on left ventricular function and
filling pressures in patients with and without congestive heart failure. Chest 2001;120:
467–73.
[71] Steens RD, Millar TW, Xialing S, et al. Effect of inhaled 3% CO2 on Cheyne-Stokes respi-
ration in congestive heart failure. Sleep 1994;17:61–8.
[72] Khayat RN, Xie A, Patel AK, et al. Cardiorespiratory effects of added dead space in patients
with heart failure and central sleep apnea. Chest 2003;123:1551–60.
[73] Szollosi I, Jones M, Morrell M, et al. Effect of CO2 inhalation on central sleep apnoea and
arousals on sleep. Respiration 2004;71:493–8.
[74] Mansfield DR, Solin P, Roebuck T, et al. The effect of successful heart transplant treatment
of heart failure on central sleep apnea. Chest 2003;124:1675–81.
[75] Poulton EP. Left sided heart failure with pulmonary plus pressure machine. Lancet 1936;2:
981–3.
[76] Barach AL, Martin J, Eckman M. Positive pressure respiration and its treatment of acute
pulmonary edema. Ann Intern Med 1938;12:754–95.
[77] Grace MP, Greenbaum DM. Cardiac performance in response to PEEP in patients with car-
diac dysfunction. Crit Care Med 1982;10:358–60.
[78] Rasanen J, Heikkila J, Downs J, et al. Continuous positive airway pressure by face mask in
acute cardiogenic pulmonary edema. Am J Cardiol 1985;55:296–300.
[79] Bersten AD, Holt AW, Vedig AE, et al. Treatment of severe cardiogenic pulmonary edema
with continuous positive airway pressure delivered by face mask. N Engl J Med 1991;325:
1825–30.
[80] Baratz DM, Westbrook PR, Shah PK, et al. Effect of nasal continuous positive airway pres-
sure on cardiac output and oxygen delivery in patients with congestive heart failure. Chest
1992;102:1397–401.
[81] Bradley TD, Holloway RM, McLaughlin PR, et al. Cardiac output response to continuous
positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992;145:377–82.
[82] DeHoyas A, Liu PP, Benard DC, et al. Haemodynamic effects of continuous positive airway
pressure in humans with normal and impaired left ventricular function. Clin Sci (Lond) 1995;
88:173–8.
[83] Liston R, Deegan PC, McCreery C, et al. Haemodynamic effects of nasal continuous positive
airway pressure in severe congestive heart failure. Eur Respir J 1995;8:430–5.
[84] Kiely JL, Deegan P, Buckley A, et al. Efficacy of nasal continuous positive airway pressure
therapy in chronic heart failure: importance of underlying heart rhythm. Thorax 1998;53:
957–62.
[85] Naughton MT, Floras JS, Rahman MA, et al. Respiratory correlates of muscle sympathetic
nerve activity in heart failure. Clin Sci 1998;95:277–85.
[86] Naughton MT, Bookman I, Floras JS, et al. Effect of CPAP on respiratory mechanics in
heart failure. Am J Respir Crit Care Med 1995;151(4):A706.
[87] Takasaki Y, Orr D, Popkin J, et al. Effect of nasal continuous positive airway pressure on
sleep apnea in congestive heart failure. Am Rev Respir Dis 1989;140:1578–82.
[88] Buckle P, Millar T, Kryger M. The effect of short term nasal CPAP on Cheyne-Stokes res-
piration in congestive heart failure. Chest 1992;102:31–5.
[89] Davies RJO, Harrington KJ, Ormerod OJ, et al. Nasal continuous positive airway pres-
sure in chronic heart failure with sleep disordered breathing. Am Rev Respir Dis 1993;
147:630–4.
[90] Kreiger J, Grucker D, Sforza E, et al. Left ventricular ejection fraction in obstructive sleep
apnea. Effects of long-term treatment with nasal continuous positive airway pressure. Chest
100;917–21.
[91] Malone S, Liu PP, Holloway R, et al. Obstructive sleep apnea in patients with dilated cardio-
myopathy: effects of continuous positive airway pressure. Lancet 1991;38:1480–4.
[92] Alchanatis M, Tourkohoriti G, Kosmas EN, et al. Evidence for left ventricular dysfunction
in patients with obstructive sleep apnoea syndrome. Eur Respir J 2002;20:1239–45.
[93] Laaban JP, Pascal-Sebaoun S, Bloch E, et al. Left ventricular systolic dysfunction in patients
with OSA syndrome. Chest 2002;122:1133–8.
[94] Artz M, Schultz M, Wenzel R, et al. Nocturnal continuous positive airway pressure improves
ventilatory efficiency during exercise in patients with chronic heart failure. Chest 2005;127:
794–802.
Crit Care Clin 24 (2008) 589–611
Nonrespiratory Sleep Disorders

Found in ICU Patients
Lee K. Brown, MDa,b,*, Madhu Arora, MDa,b
a
Program in Sleep Medicine, University of New Mexico Health Sciences Center, 1101 Medical
Arts Avenue NE, Building #2, Albuquerque, NM 87102, USA
b
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine,
University of New Mexico School of Medicine, 5-ACC, MSC10-5550,
Albuquerque, NM 87131-0001, USA
Sleep, critical illness, and intensive care

When sleep/wake factors are considered in the ICU, the discussion fre-
quently does not advance beyond matters pertaining to sleep-disordered
breathing. As can be seen from the other articles in this issue, sleep-disor-
dered breathing is undoubtedly a major issue in the ICU. There are myriad
sleep/wake disorders that afflict humankind, however, and admission to the
ICU does not necessarily mask their presence. Indeed, many such disorders
are aggravated, or even triggered, by the ICU experience. That experience
includes sleep-disruptive environmental factors, the multitude of psychoac-
tive drugs (or those potentially psychoactive because of side effects) that are
commonly used, and the effects of the specific critical illness itself.
Environmental factors leading to sleep deprivation in hospital patients
remain a problem, particularly in the ICU. Although the Environmental
Protection Agency recommends that noise levels in the hospital not exceed
45 dB(A) in the day and 35 dB(A) at night [1], and the World Health
Organization more recently promulgated even more stringent standards
[2], several studies have shown the presence of consistently higher levels in
various hospital settings because of respirator alarms, bedside monitors,
infusion alarms, and conversations among staff, with little or no reduction
in noise volume at night [3–5]. A paper imaginatively titled ‘‘Name that
TonedThe Proliferation of Alarms in the Intensive Care Unit’’ [6] singled
* Corresponding author. Program in Sleep Medicine, University of New Mexico Health

Sciences Center, 1101 Medical Arts Avenue NE, Building #2, Albuquerque, NM 87102.
E-mail address: lkbrown@alum.mit.edu (L.K. Brown).
590 BROWN & ARORA
out audio signals in the ICU as a major source of this noise. Furthermore,
the investigators noted that physicians, nurses, and respiratory therapists
could correctly identify only one half of the alarms that were deemed critical
in nature, suggesting that a more reasoned approach to the volume and
number of alarms might make them more effective while reducing the over-
all noise level. In addition to alarm noise, factors that are known to add to
the din include mechanical noise from ventilators and other respiratory ther-
apy equipment, audio from televisions, conversations (between or among
staff, patients, or visitors, in person or over the telephone or intercoms),
paging systems, and heating/ventilation/air conditioning systems [3]. Added
to the disrupting influence of ambient noise, ICU patients may also be
subjected to levels of nighttime room illumination that potentially could
interfere with sleep in some patients and that are ill timed with respect to
circadian physiology [4,7,8]. Although available data suggest that ICU light-
ing at night is substantially less than during the day, the levels measured
(up to an average maximum of almost 1500 lux in one study) are still capa-
ble of affecting circadian phase [4,8]. Too much light at night is also consis-
tently ranked by patients as a stressful factor during their ICU stay [7,9–12].
Other environmental causes of sleep disruption in the ICU include nursing
interventions (taking of vital signs, delivering of medications, equipment
checks and adjustments) and procedures, in particular those that may occur
during the night or early morning, such as phlebotomy (often performed
toward the end of the normal sleep period so that results are ready for morn-
ing rounds) [4,7,10,12–14].
In addition to these environmental aspects, there are numerous disease-
related or patient-related factors that can disrupt or alter sleep. These
include mechanical ventilation [15–18], stress and pain [10,12,19], and
a host of medications commonly used in the ICU that include classes as
diverse as corticosteroids, b-adrenergic antagonists, antiepileptics, opiates,
pressors, nonsteroidal anti-inflammatory drugs, fluoroquinolone antibi-
otics, and antiretroviral agents [20–24]. Withdrawal from drugs that were
part of a patient’s usual therapeutic regimen but were discontinued in the
ICU can also adversely affect sleep [20], as can nicotine withdrawal in the
premorbid user of tobacco [25]. Polysomnographic studies performed in
the ICU [14,15,17,26–28] and in women exposed to a simulation of ICU
noise [29] confirm decreases in sleep efficiency, total sleep time, and stage
rapid eye movement (REM), and increases in arousals and awakenings.
One study of ICU patients also suggested that sepsis (either ongoing or
up to 8 hours prior to development of clinical sepsis) was associated with
characteristic EEG findings (mixed frequency, low-voltage pattern with
intermittent theta and delta activity) that could not be interpreted as un-
equivocal wake or sleep [26]. Other studies have suggested that critically
ill patients exhibit increased amounts of delta activity, but no correlation
with sepsis could be demonstrated [15,17]. Explanations that have been
posited, but not proven, include septic encephalopathy or the effects of
NONRESPIRATORY SLEEP DISORDERS FOUND IN ICU PATIENTS 591
cytokines elaborated as part of the inflammatory response to infection (eg,

interleukin-1 or tumor necrosis factor) [17].
In view of the diverse factors that profoundly affect sleep in the ICU pa-
tient, it is intuitive that various sleep disorders may emerge or worsen under
the eyes of the intensivist. Unfortunately, relatively few sleep/wake disorders
have been the focus of systematic study in the ICU patient, with sleep-
disordered breathing (discussed in articles elsewhere in this issue) and
ICU delirium leading the list. This focus is not surprising, given that inves-
tigations into life-and-death issues that are commonplace in the ICU must
necessarily capture the most attention. Consequently, much of the following
discussion is limited to reasoned conjecture rather than based on actual
data. Regardless, critical care practitioners should be aware of these sleep/
wake disorders and have a working knowledge of how to treat them.
Parasomnias
Parasomnias are defined in the second edition of the International Clas-
sification of Sleep Disorders (ICSD-2) as ‘‘undesirable physical events or ex-
periences that occur during entry into sleep, within sleep, or during arousals
from sleep’’ [30]. These disorders are further subclassified into those associ-
ated with arousal from non-REM sleep (confusional arousals, sleepwalking,
and sleep terrors), those associated with REM sleep (REM sleep behavior
disorder, recurrent isolated sleep paralysis, and nightmare disorder), and
‘‘other.’’ The latter consists of a wide variety of sleep-related behaviors, in-
cluding enuresis, catathrenia (groaning), hallucinations, eating, and various
sorts of dissociative states. The medical literature is noticeably sparse with
respect to reports of parasomnias in the ICU, actually consisting only of
one paper by Schenck and Mahowald [31] reporting their experience diag-
nosing and treating REM sleep behavior disorder (RBD), sleepwalking,
and sleep terrors in this population. They described 20 patients accumulated
during 8 years of sleep medicine practice who had an active, undiagnosed,
and untreated parasomnia as part of their ICU stay. Three types of para-
somnia–ICU relationships were identified: parasomnias associated with
a cerebrovascular accident and first manifest on ICU admission (3 patients),
ICU care made necessary because of an injury sustained during a parasom-
nia (2 patients), and parasomnias complicating an ICU admission for an
unrelated medical problem (15 patients). All 20 patients underwent compre-
hensive polysomnographic studies that were diagnostic for RBD or for
sleepwalking/sleep terrors. All 3 of the stroke patients had RBD; of the
patients admitted with parasomnia-related trauma, 1 had RBD and 1 had
sleepwalking/sleep terrors. All patients who manifest a parasomnia in-
cidental to their stay in critical care had RBD except for 2 diagnosed with
sleepwalking/sleep terrors.
For various reasons, it is not particularly surprising that no other reports
of an ICU–parasomnia relationship are available. Abnormal patient
592 BROWN & ARORA
behaviors are often simply attributed to ICU psychosis by ICU staff and
physicians. Also, many ICU patients are sedated (and often pharmacologi-
cally paralyzed), thus inhibiting any overt manifestations of a parasomnia;
even if not sedated/paralyzed, the limited autonomy of the ICU patient
because of illness severity, various tubes and catheters, and restraints can
make such behaviors difficult to distinguish. The following discussion con-
centrates on RBD and sleepwalking/sleep terrors (as reported by Schenck
and Mahowald) and more lightly touches on other parasomnias most likely
to be encountered in the ICU.
Rapid eye movement sleep behavior disorder

The existence of REM sleep behavior disorder was presaged in 1965 by
experiments in the cat reported by Jouvet and Delorme [32]. They demon-
strated that lesions in the pontine tegmentum could induce what appeared
to be physical enactment of dreams in an animal showing electrophysiologic
evidence of sleep: tracking a nonexistent object, attacking imaginary prey,
and flight from an illusory aggressor. Subsequent work revealed that so-
matic muscle atoniadone of the defining features of REM sleepdstems
from an active process of motor neuron inhibition involving specific
pontine and medullary nuclei [33]. Undoubtedly, the suppression of
dream-related muscle activity (ie, acting out of dream mentation) provided
a significant evolutionary advantage. Schenck, Mahowald, and colleagues
[34] were the first to recognize the clinical correlate of Jouvet’s lesioned
cats in their seminal description of RBD, published in 1986. They described
the occurrence of behaviors consistent with enactment of dream mentation
in five elderly individuals, and confirmed polysomnographically that these
episodes occurred during REM sleep. Interestingly, four of their original
five patients suffered from significant neurologic disease. Actions such as
punching, yelling, swearing, kicking, screaming, grabbing, talking, running,
crawling, and jumping out of bed are commonly described, and when such
patients awaken they usually report an isomorphic dream consistent with
the observed movements [35]. The dreams themselves are usually action-
packed, often involving fleeing from pursuit or fending off an attacker,
and are frequently described as being inconsistent with the patient’s typi-
cally sedate demeanor. Because this behavior occurs during REM sleep,
episodes are more common in the latter half of the night, consistent with
the circadian rhythm of REM propensity. Furthermore, most RBD cases
present after the age of 50 and the disease occurs more commonly in
men than in women.
RBD in humans occurs in an acute and a chronic form. The acute form
can be seen during alcohol withdrawal, in patients receiving tricyclic an-
tidepressants, monoamine oxidase inhibitors, cholinergic agents, and the
selective serotonin reuptake inhibitors, and with excessive caffeine and
chocolate ingestion [36]. Perhaps more pertinent to the ICU patient are
reports of RBD provoked by administration of b-adrenergic antagonists

(eg, bisoprolol) or the analgesic drug tramadol [37,38]; also, RBD can
ensue on withdrawal from benzodiazepines or alcohol intoxication [37].
The b-adrenergic antagonists and tramadol are known to significantly affect
REM sleep, perhaps accounting for their association with RBD [38–41]. The
chronic form of RBD is most often idiopathic or associated with neurologic
disorders. Reports of RBD exist in association with cerebrovascular events
(as described in Schenck and Mahowald’s ICU series [31]), pontine neo-
plasm, Tourette syndrome, and normal pressure hydrocephalus [30], but
the most robust associations have been reported for various degenerative
neurologic disorders, particularly Parkinson disease and other diffuse
Lewy body diseases [42–45]. These disorders share a histopathologic feature
consisting of a-synuclein deposits in and around neurons and glial cells.
These insoluble aggregates of protein presumably induce cell death in sus-
ceptible areas of the central nervous system, leading to the specific symp-
toms associated with each disorder. In addition to Parkinson disease,
these entities include the multiple system atrophies or ‘‘Parkinson-plus’’ syn-
dromes (Shy-Drager syndrome, olivopontocerebellar degeneration, and
striatonigral degeneration), Lewy body dementia, and Lewy body variant
of Alzheimer disease. Strikingly, the multiple system atrophies and Lewy
body dementias have an incidence of RBD preceding, emerging with, or fol-
lowing the disease approaching 100% [36,37,45–47], and Parkinson disease
has been seen to develop after the onset of chronic idiopathic RBD in more
than one third of patients [42]. Other degenerative disorders linked to RBD
include Alzheimer disease, progressive supranuclear palsy, Alzheimer dis-
ease associated with Down syndrome, group A xeroderma pigmentosum,
mitochondrial encephalomyopathy, demyelinating disorders (multiple scle-
rosis, Guillain-Barré syndrome), spinocerebellar ataxia type 3, and narco-
lepsy [30]. Some of these disorders, particularly stroke [31], Guillain-Barré
syndrome, and the various common neurodegenerative disorders, frequently
require acute care for the disorder itself or for pulmonary complications,
and the ICU practitioner should be alert to the possibility of RBD emerging
in these individuals.
The diagnosis of RBD is made by demonstrating, during polysomnog-
raphy, excessive EMG tone during REM sleep in submental or limb leads
along with either a history of sleep-associated behaviors consistent with
RBD or direct observation of these behaviors [30]. If full polysomnogra-
phy is not available (as is the case in most inpatient facilities), portable
electroencephalography (EEG) can almost always be arranged and may
serve as a limited form of polysomnography if EMG electrodes are added
to the montage. The practitioner should also rely on expert guidance
from a sleep medicine consultant, who may be able to elicit a history
from family members that, along with physical findings and direct obser-
vation of episodes, could provide compelling evidence supporting the
diagnosis.
594 BROWN & ARORA
The first-line treatment of RBD is administration of clonazepam; it is

effective in nearly 90% of cases and with minimal toxicity [31,34–37,48].
The usual dose varies between 0.25 mg and 2.0 mg at bedtime. For patients
who cannot take medications by mouth or feeding tube, parenteral
benzodiazepines (eg, lorazepam intramuscularly or intravenously [IV] or
diazepam IV) can be considered, although data supporting therapeutic
equivalence with clonazepam for this indication are slim [31,48]. Melatonin
(initially 3 mg at bedtime, titrating up to 12 mg as necessary) and pramipex-
ole (starting with 0.25 mg and titrating up to 1.5 mg, either in a single
bedtime dose or divided between evening and bedtime doses) have emerged
as alternative, second-line agents [37,49–53], although again, parenteral
formulations are not available. There is an additional complication with
melatonin: although a United States Pharmacopeia (USP) standard exists,
no products meeting the standard (ie, carrying the USP Verified Dietary
Supplement label) are currently listed on the USP Web site [54]. Ramelteon,
a Food and Drug Administration (FDA)–approved melatonin receptor ag-
onist is available for the treatment of insomnia, but no data are available
concerning its efficacy in RBD. Management of RBD in the ICU should in-
clude review of the patient’s medication list and discontinuation of any
drugs that are known to worsen or provoke the parasomnia if at all possible.
The many disruptors of sleep in the ICU should be minimized because their
presence during REM sleep can provoke RBD episodes. Similarly, sleep-
related breathing disorders occurring during REM sleep can lead to bouts
of RBD and should be identified and treated. Finally, treatment consider-
ations for RBD (and violent parasomnias in general) in any setting must
include maintenance of as safe an environment as is practical, and restrain-
ing the patient when necessary to prevent injury.
Sleepwalking (somnambulism) and night terrors

Sleepwalking and sleep terrors are classified as arousal parasomnias,
meaning that they are generally associated with arousal, or incomplete
arousal, from non-REM sleep [55]. Sleepwalking is most commonly seen
in childhood, with a reported prevalence as high as 17% [55,56]. The dis-
order not infrequently persists into adulthood, with prevalence estimates
ranging between 2% and 4% [56–58]; the de novo appearance of somnam-
bulism in adults is also not uncommon [57,59]. Somnambulism exhibits
a strong familial predisposition [57], and an association has been detected
with HLA DQB1*05 and *04 alleles [60]. Patients demonstrate sudden au-
tomatic behaviors that may include wandering around the room, sitting up
in bed, or moving objects around their environment [61]. Behaviors may
consist of routine activities that are normal except for their timing (driving,
eating), or may be inappropriate (urinating outside of the lavatory, violent
or aggressive behavior, sexual conduct) [30,61–63]. Sleepwalkers are
not generally communicative during the event as they have limited or no
consciousness, despite their eyes usually being open [30]. Awakening

a sleepwalker should be avoided because it can cause confusion or even
aggressive behavior [64]; sleepwalkers often tend to go back to bed by
themselves, but may awaken in unusual or unexpected locations [30,63].
Little or no dreaming is reported, and most individuals are amnesic for
the episode [30,61].
Sleep terrors (also called night terrors or pavor nocturnus) are character-
ized by an apparent sudden awakening from sleep, accompanied by a loud
cry and outward signs of panic, autonomic arousal (fight or flight re-
sponse), and behavior consistent with escaping from a frightening situation
[30]. The intense autonomic component consists of tachycardia, tachypnea,
diaphoresis, and mydriasis [30,61,62]. The patient is disoriented and con-
fused on awakening and does not have memory of the event, but may recall
dreamlike fragments with frightening imagery [30]. Contact with an indi-
vidual during a sleep terror can provoke violent behavior as with sleep-
walking [64]. Estimated prevalence is about 6% in children [62], but as in
other arousal parasomnias, sleep terrors are more common in adults
than generally acknowledged (approximately 2%); a family history of sleep
terrors or other arousal parasomnias is frequently present [30]. Diagnosis
of the arousal parasomnias usually is based on a characteristic history,
but formal polysomnographic studies that include an expanded EEG mon-
tage and continuous audiovisual monitoring may be necessary in some
cases. As in the case of suspected RBD, expert sleep medicine consultation
and portable EEG recordings constitute the most practical evaluation strat-
egy when polysomnography with video recording is not available in the ICU.
Where normal sleep–wake patterns are established (eg, outside of the
hospital), arousal parasomnias usually occur in the first third of the night
when most stage N3 (slow-wave sleep) is experienced, although one report
suggests that this maxim may not hold true in adults [65]. Controversy con-
tinues as to whether polysomnographic recordings in patients prone to
arousal parasomnias more commonly demonstrate greater fragmentation
of non-REM sleep (particularly N3) or bouts of hypersynchronous delta
EEG activity than individuals who do not have a parasomnia; these phe-
nomena, along with a marked increase in EEG delta activity consistent
with N3 sleep, have also been reported to occur immediately before an ep-
isode of arousal parasomnia [63,66–73]. During and immediately after an
episode, EEG findings of synchronous diffuse delta are most common
[30,68,74], although other patterns have also been reported, particularly in
events arising out of N2 sleep: admixtures of diffuse delta, with theta, alpha,
and beta activity; and combinations of alpha and beta activity alone [68].
The pathogenesis of sleepwalking and sleep terrors is unknown, although
most theories allude to incomplete central nervous system (CNS) arousal,
including deficient cortical activation, as indicated by the presence of delta
EEG activity or other EEG evidence of continued cortical sleep during
events [30,61,63,74]. Support for this theory is available from one case
596 BROWN & ARORA
report of single photon emission computed tomography in a patient who

had sleepwalking, which demonstrated activated thalamocingulate connec-
tions while other thalamocortical arousal pathways remained quiescent
[75]. Also, a recent study of transcranial magnetic stimulation in sleep-
walkers found that some cortical inhibitory circuits had reduced excitability
compared with normal controls, predominantly involving GABAa and cho-
linergic circuits [76].
As is also the case with RBD, there are numerous risk factors often pres-
ent in the ICU that are known to exacerbate the arousal parasomnias. These
include sleep disruption and deprivation, fever, stress (physical or emo-
tional), sleeping in an unfamiliar location, and exposure to noise or light
[30,61,63,72]. A wide variety of medications, along with alcohol, have also
been implicated as factors in promoting or worsening arousal disorders, in-
cluding zolpidem, phenothiazines, quetiapine, anticholinergic agents, lith-
ium, bupropion, and topiramate [30,63,77–79]. One reviewer makes the
not-unreasonable claim that virtually any psychotropic medication may be
capable of inducing an arousal parasomnia in susceptible individuals [61].
Thyrotoxicosis, an entity that not infrequently requires ICU care, has
been associated with sleepwalking in a case series of eight patients [80].
Arousal disorders can also complicate neurologic disease, including Parkin-
son disease, migraine, head trauma, encephalitis, Tourette syndrome, and
stroke [30,63,81]. Several primary sleep disorders may also provoke arousal
parasomnias, including periodic limb movement disorder, sleep apnea, and
even treatment of sleep apnea with continuous positive airway pressure
[30,58,82–85]. Finally, psychiatric pathology has long been suggested as
a contributing factor for arousal parasomnias in adults, although substan-
tial arguments have been made both for and against this point of view
[30,59,62,86–88].
Treatment in the outpatient setting is often not necessary. Reassurance
that the episodes are typically benign, lack psychologic significance, and
will diminish over time can be all that is needed, although maintenance of
a safe environment and limiting the patient’s ability to leave the bedroom
are key elements of management. If the actions put the patient in a danger-
ous situation, as may well occur in the ICU, treatment should be considered.
First and foremost, interventions that render the patient’s environment
more conducive to sleep should be considered. Next, treatment of concom-
itant sleep disorders, such as sleep apnea or periodic limb movement disor-
der, would clearly be in order [85]. Benzodiazepines (including clonazepam
or diazepam, up to 5 mg of either) taken an hour before sleep onset are
usually effective [31,61,89,90]. Paroxetine, imipramine, and trazodone
have been reported to be effective in isolated disorders of arousal, and other
serotonin reuptake inhibitors may be useful also [61,63,85,91–94]. Non-
pharmacologic treatment, such as psychotherapy, progressive relaxation,
or hypnosis, have been shown to have modest usefulness at best, and regard-
less would be of limited applicability in the ICU setting [63,85,89].
Nightmare disorder
Nightmare disorder (ND) is a REM sleep parasomnia characterized by
recurrent awakenings with recall of frightening or disturbing dreams. The
patient is typically fully alert on awakening, and the nightmares tend to oc-
cur most commonly during the final third of the night when the circadian
rhythm of REM propensity is highest [30]. Nightmare disorder is closely as-
sociated with acute stress disorder (ASD) and posttraumatic stress disorder.
In the ICU, ASD is highly prevalent and therefore a high incidence of ND
would be expected, although it may often be attributed to ICU psychosis
(also called ICU delirium and ICU syndrome) rather than separately noted.
The following discussion concentrates on the specific sleep disorder of ND
rather than a general discussion of ICU psychosis, because the latter entity
is not part of the nosology of sleep disorders [30].
Nightmares are commonly reported by patients struggling to survive life-
threatening conditions in the ICU [95–98]. The vivid nightmares often con-
vey feelings of extreme horror, dread, or impending mortality, and their
content may depict the patient’s afflictions, agonizing treatments, isolation,
dependency, and the real possibility of death. One assessment of traumatic
ICU memories reported by 80 patients who had acute respiratory distress
syndrome found that nightmares were by far the most frequently remem-
bered adverse event [97]. They were described to be far more common
than any of the other three types of trauma evaluated: anxiety, pain, and re-
spiratory distress. A study of critically ill patients requiring intubation,
ventilation, and sedation found that length of stay in the ICU was the
best predictor of nightmares [95]. Of the 127 patients who stayed for more
than 1 day, 23 (18%) reported nightmares and 18 (14%) remembered hallu-
cinations. Of the 162 patients who stayed less than 24 hours, 4 (2.5%) re-
ported nightmares and 1 (0.6%) reported hallucinations. Furthermore,
a wide variety of medications are associated with an increased likelihood
of nightmares, many of which are commonly used in the ICU. A systematic
review of this issue reported that the most likely drug classes causing night-
mares are sedative-hypnotics, b-adrenergic antagonists, dopamine agonists,
and amphetamines [99], whereas other reviewers have implicated additional
classes of drugs, such as cholinergics (eg, carbachol, donepezil), neuroleptics
(eg, thiothixene) and selective serotonin reuptake inhibitors (eg, fluoxetine,
paroxetine) [22]; withdrawal from REM sleep-suppressing agents can also
induce ND [30]. Finally, ND is reported to be more common in women,
in patients who have behavioral health disorders, and in individuals of
low socioeconomic status [30].
Treatment of ND consists of behavioral and pharmacologic measures
[100]. Behavioral techniques include imagery rehearsal therapy, relaxation
techniques, and attention to sleep hygiene. In the ICU, modification of those
factors that lead to sleep disruption would be appropriate. Pharmacologic
treatment typically involves the use of benzodiazepine receptor agonists.
598 BROWN & ARORA
Circadian rhythm disorders

It has long been known that many physiologic processes in humans and, in
fact, in organisms as primitive as Drosophila, vary over an approximately
24-hour cycle known as the circadian rhythm. Attributes as diverse as core
body temperature, renal function, bronchomotor tone, and a panoply of
endocrine hormones are governed by circadian factors [101]. Research in
laboratory animals identified the suprachiasmatic nucleus (SCN) of the hy-
pothalamus as the location of the principle circadian pacemaker in mammals
[101]. Furthermore, investigations that involve placing laboratory subjects
(including humans) into environments without time cues (zeitgebers), such
as light or regular meal times (a situation known as ‘‘free-running’’), have
demonstrated that the SCN pacemaker follows a period that can vary
significantly from 24 hours [101]. Resetting of the SCN is achieved by envi-
ronmental zeitgebers, the most important being exposure to bright light at
the proper time of day (morning) and, less effectively, by regular meal times
or other activities. More recently, major breakthroughs in cell molecular bi-
ology have resulted in a detailed understanding of the mechanisms by which
the circadian pacemaker keeps time. The mechanism involves an autoregula-
tory feedback loop in which transcription of three genes results in protein
products that inhibit transcription of their own parent genes, thus establish-
ing a periodic oscillation in SCN neural activity [102].
Circadian rhythm disorders occur when the circadian timekeeping system
malfunctions or loses synchrony between the normal, or desired, sleep–wake
cycle [103]. These circadian rhythm disorders are considered part of the
nosology of sleep disorders because two important sleep–wake properties
are governed by the circadian pacemaker: an alerting mechanism that coun-
teracts homeostatic sleepiness, and the propensity to enter REM sleep
[103–105]. When the circadian pacemaker malfunctions or is not synchro-
nized with the normal or desired sleep–wake cycle, two of the cardinal symp-
toms of sleep disorders can occur: insomnia, if the circadian clock is driving
an individual’s wakefulness when sleep is desired; and excessive sleepiness, if
circadian alerting is on the wane when the individual desires to be awake
and alert [30,105]. These entities include jet lag, shift work, and delayed, ad-
vanced, irregular, and free-running types of circadian rhythm disorders
[30,106–109]. Presumably, any or all of these disorders might occur in the
ICU patient given the loss or disruption of environmental zeitgebers. In ad-
dition, critical illness itself has been shown to disrupt circadian timekeeping
[110,111]. Indeed, multiple studies using several metrics for gauging circa-
dian phase have demonstrated that SCN rhythmicity is severely impaired,
if not extinguished, in the ICU [112–115]. One study, using skin potentials
as an index of sleep or arousal levels, demonstrated that circadian rhythmic-
ity is lost, on average, by the fifth ICU day [115].
Loss of the circadian timekeeping function can be expected to disrupt the
sleep–wake cycle and impair the patient’s ability to achieve consolidated
sleep, when desired, and remain awake and alert at other times. This impair-
ment in turn may promote ICU psychosis; in addition, the loss of circadian
timekeeping for other physiologic functions, such as endocrine hormone
secretion, can be expected to interfere with the treatment of disease. In
the ambulatory setting, for example, circadian rhythm disorders, such as
that of the shift work type, have been shown to promote peptic ulcer disease
and interfere with glycemic control in diabetics [116–119].
Treatment of circadian rhythm disruption in the ICU is generally recog-
nized as centered on ameliorating the environmental factors detailed above
[8,14,120–122]. These include techniques that reduce noise, including staff
education, elimination of overhead paging through the use of wireless tech-
nology, and initial ICU design or renovation [3,8,123,124]. In addition, to
help counter circadian disruptors in the ICU, attention should be paid to
the scheduling and intensity of light exposure consistent with our knowledge
of circadian principles, and (when possible) better scheduling of patient
interventions [8]. Melatonin, to promote circadian entrainment and as a hyp-
notic, has been advocated for use in the ICU, but with inconsistent results
[125,126]. The choice of mode in mechanically ventilated patients also
seemed to make a difference in a recent study; assist-control ventilation,
rather than pressure support ventilation, resulted in reduced wakefulness
and increases in all stages of sleep as measured by polysomnography [16].
Finally, complementary and alternative therapies consisting of massage,
music therapy, ocean sounds, white noise, earplugs, and therapeutic touch
have been advocated on the basis of limited, but promising, clinical studies
[127–130].
Sleep-related movement disorders

The most recent definition of sleep-related movement disorders limits this
designation to stereotyped or relatively uncomplicated movements that ac-
company sleep and are not related to another primary sleep disorder [30].
The most common of these disorders to become apparent in the ICU would
likely include restless legs syndrome (RLS), periodic limb movement disor-
der (PLMD), sleep-related leg cramps, and possibly sleep-related bruxism
and sleep-related rhythmic movement disorder.
Restless legs syndrome and periodic limb movement disorder

RLS was first described in the medical literature by Ekbom [131] almost
50 years ago. Fundamental manifestations of RLS include an unpleasant
sensation (dysesthesia) that affects primarily the legs (but may involve the
arms or trunk); temporary relief with movement, such as walking or stretch-
ing; and circadian variation in the intensity of symptoms, which are most
apparent in the evening or at night [132]. RLS frequently interferes with
sleep onset. This property accounts for its designation as a sleep disorder,
600 BROWN & ARORA
and the close association of RLS with PLMD explains its inclusion under
the movement disorder category [30]. There continues to be some contro-
versy as to whether RLS and PLMD are manifestations of the same under-
lying disease or are separate but related disorders, but this distinction is of
more academic interest than clinical usefulness. RLS is reported to affect up
to 10% to 15% of the adult population, although the number of individuals
who have symptoms troublesome enough to require treatment is lower, at
around 3% [133–135]. The prevalence of RLS increases with age and is gen-
erally higher in women than men (except women who have no history of
pregnancy). In addition to a high frequency of idiopathic and familial
RLS, persuasive data are available demonstrating that RLS can be second-
ary to iron deficiency [136], renal insufficiency [137], pregnancy [138], and
spinal cord disease [139]. Many other associations between RLS and medi-
cal disorders or medication usage are widely quoted but remain controver-
sial or anecdotal. In view of current theories of RLS pathogenesis involving
deficient CNS dopaminergic activity, the notion that dopamine antagonists
provoke RLS has significant face validity [30]. One small but well-performed
challenge study failed to confirm such a relationship, however [140]. Antide-
pressant medications (tricyclics and serotonin reuptake inhibitors, except for
bupropion) are said by many to worsen RLS, but the evidence for this is also
contradictory [30,141,142]. In view of these associations, RLS can presum-
ably be exacerbated in the ICU setting because of coexisting iron deficiency,
uremia, the use of certain medications, and prolonged immobilization.
Consequently, it is incumbent on the ICU practitioner to at least consider
the possibility of RLS in the patient who appears combative, restive, or ag-
itated. In one recent report, severe RLS has been implicated as inducing
such uncontrolled attempts at ambulation that multiple skeletal injuries
were sustained [143].
Periodic limb movement disorder manifests as repetitive, stereotyped
movements during sleep, almost always involving the legs rather than the
arms, in a manner that simulates the Babinski reflex (extension of the
toes, flexion of the ankle, knee, and sometimes the hip) [30]. These move-
ments are common as an incidental finding on polysomnography and are
considered pathologic only if accompanied by a nocturnal sleep disturbance
(recurrent awakenings) or daytime symptoms (unrefreshing sleep, excessive
daytime sleepiness) [30]. Most patients who have RLS demonstrate PLMD
on polysomnography, and there is also a strong association between PLMD
and both RBD and narcolepsy. Virtually all of the inciting factors for RLS
enumerated above have been implicated as provoking PLMD also. The im-
portance of recognizing PLMD for the ICU practitioner mainly concerns
the need to distinguish these movements from myoclonus attributable to
serious neurologic disease or metabolic derangements.
Clues about the pathogenesis of RLS and PLMD were initially provided
by the response of these disorders to dopamine and opiate agonist medica-
tions, which suggested a derangement of CNS dopaminergic or opiatergic
circuits. Subsequent work using positron emission tomography has impli-

cated nigrostriatal dopaminergic dysfunction [144,145]. Also, rats receiving
6-hydroxydopamine injections (a neurotoxin that lesions dopaminergic
pathways) into diencephalic A11 dopaminergic neurons exhibited behavior
consistent with RLS that could be reversed with pramipexole [146]. Further-
more, the relationship between iron deficiency, reduced serum ferritin, and
RLS can be explained in terms of CNS dopamine depletion in that iron is
a required cofactor for dopamine production, and several studies have
demonstrated decreased substantia nigra iron stores in patients who have
RLS compared with controls [147–149].
Four categories of medications contain agents that are commonly pre-
scribed to treat RLS: dopamine agonists, anticonvulsants, opioids, and ben-
zodiazepine receptor agonists. Dopamine agonists are widely recommended
as first-line treatment, and three agents predominate: carbidopa/levodopa,
pramipexole, and ropinirole [150,151]. Other agents, such as bromocriptine,
pergolide, and cabergoline, have demonstrated efficacy but are either no
longer available or carry an unacceptable risk for side effects compared
with the non–Ergot-derived drugs. Carbidopa/levodopa is used predo-
minantly in mild cases, at doses of 25 mg/100 mg of either the regular or
controlled-release formulation. This agent is well known for inducing aug-
mentation (worsening of symptoms on the day after an evening dose) and
rebound (worsening symptoms in the early morning after an evening dose)
in a substantial proportion of patients. Pramipexole and ropinirole are two
non–Ergot-derived agonists that have been shown to possess sustained
efficacy in the treatment of RLS and carry FDA-approved labeling for
this disorder. Both of these drugs are well tolerated, and adverse effects
are usually dose related, mild, and limited to nausea, lightheadedness,
and fatigue; these usually subside within 2 weeks. Less frequent side effects
include nasal stuffiness, constipation, insomnia, and leg edema. Sudden, un-
expected sleep attacks have been reported with virtually all of the common
dopamine agonists, independent of dose and duration [152]. These drugs
typically start acting 90 to 120 minutes after ingestion and therefore are
usually administered about 2 hours before RLS symptoms start in any in-
dividual patient. Initial recommended dosing is 0.125 mg for pramipexole,
and may be increased by 0.125 mg every 2 to 3 days until an adequate effect
is obtained. Ropinirole is used at a starting dose of 0.25 mg and may be
increased by 0.25 mg every 2 to 3 days [150]. Gabapentin is the anticonvul-
sant most commonly used for management of RLS. A well-performed
clinical trial demonstrated efficacy with a regimen that started at 100 mg
to 300 mg in the evening or at bedtime followed by titration upward to
an optimal mean dose of about 1800 mg [150,153]. In the ICU, gabapentin
can be a good choice because of its favorable side-effect profile (mainly se-
dation, which can be a problem in outpatient use) and its availability as an
oral solution. Opiates ranging in potency from propoxyphene or codeine up
through methadone, and the opiate agonist tramadol, are effective in RLS
602 BROWN & ARORA
with the specific agent chosen on the basis of severity [150]. Multiple ben-
zodiazepine receptor agonists have been reported to be helpful, particularly
in mild disease; drugs that have been used include clonazepam (most fre-
quently reported), temazepam, zolpidem, zaleplon, and triazolam [150].
The choice of a specific agent depends on the available route of administra-
tion and desired pharmacodynamics. Treatment of iron deficiency can com-
pletely resolve all RLS symptoms in some patients. Iron replacement is
recommended if the serum ferritin level is less than 45 to 50 mg/mL [150].
The suggested regimen is ferrous sulfate 325 mg three times daily in combi-
nation with vitamin C (to enhance absorption), 100 to 200 mg with each
dose of iron. Parenteral iron dextran has been advocated for particularly
severe or resistant RLS; to date, efficacy has been demonstrated in one ran-
domized controlled trial in patients who had end-stage renal disease [154].
Magnesium, which is attractive for use in the ICU because of availability in
a parenteral form, has reported usefulness but only in a small, open pilot
study [155].
Nonpharmacologic measures for ameliorating RLS that are of possible
use in the ICU include maintenance of good sleep hygiene; activities that
could divert the patient’s attention from the symptoms, such as video games
or puzzles; and enhanced external counter pulsation, applied to the legs for
1 hour per day in one study [143,156].
Sleep-related leg cramps

A muscle cramp is defined as a sudden, painful contraction of a muscle or
muscle group [157]. These events may occur during wakefulness or arise
from sleep, and are usually relieved by stretching the affected muscle.
Cramps that regularly awaken a patient from sleep are included under the
rubric of sleep-related movement disorders in the ICSD-2 [30]. Muscle
cramps can be idiopathic (particularly in the elderly) or may arise from
lower motor neuron disease, metabolic derangements (hypovolemic hypona-
tremia, hypothyroidism, hypoadrenalism, uremia, end-stage liver disease),
pregnancy, and as a side effect of certain medications (b-adrenergic agonists,
statins, clofibrate, and diuretics) [157]. Cramps are also common following
exercise, particularly in muscles naı̈ve to overuse, and may be a result of in-
jury, accumulation of metabolic waste products, dehydration, or electrolyte
shifts (sodium or potassium) in the involved muscle [157]. Treatment con-
sists of stretching, splinting of the area prone to cramping, and optimal
management of any underlying disorder or metabolic derangement. Quinine
sulfate has long been advocated for treatment of muscle cramps, but con-
cerns about thrombocytopenia and cinchonism have led most clinicians to
abandon its use. Other medications that may be considered include sodium
channel blockers, such as phenytoin or carbamazepine, but the high risk/
benefit ratio of these agents when used for a relatively benign disorder
must be carefully weighed [157].
Sleep-related bruxism
Bruxism may consist of tooth grinding or rhythmic masticatory muscle
activity, and when it occurs in association with sleep or arousal from sleep
it is counted as a sleep-related movement disorder [30]. Sleep-related brux-
ism (SRB) is most common in children, has a tendency to be familial, and
may occur in adults, in whom it is said to be associated with the type A per-
sonality [30,62]. Other than discomfort experienced by those subjected to the
sounds of SRB, the most important sequelae consist of dental trauma, tem-
poromandibular joint disease, and masseter muscle hypertrophy. In the
ICU, SRB could potentially result in damage to orotracheal tubes or other
devices. Treatment, when necessary, consists of a dental prosthesis that
cushions and limits the injurious behavior.
Sleep-related rhythmic movement disorder

Also known as body rocking, head banging, head rolling, or body rolling,
these self-descriptive behaviors are repetitive, rhythmic, and stereotyped
movements occurring during drowsy wakefulness or light sleep [30]. Sleep-
related rhythmic movements are common in infants and young children,
progressively declining in prevalence such that they are only rarely seen in
adults except in cases of developmental impairment [62]. The behaviors
are only considered pathologic if injury, daytime sleepiness, or sleep disrup-
tion ensues, at which point the appellation rhythmic movement disorder
becomes applicable. The movements occur with a frequency between 0.5
and 2 per second and are believed to provide vestibular stimulation that
the individual perceives as soothing. Treatment mainly consists of padding
the sleeping environment or other safety precautions, although benzodiaze-
pines can be used when necessary [158].
Hypersomnias of central origin

The prototypical member of this category is narcolepsy, a neurologic dis-
order characterized by excessive daytime sleepiness [30]. Two subtypes of
narcolepsy are now recognized: narcolepsy with cataplexy and narcolepsy
without cataplexy. Cataplexy is defined as a sudden loss of muscle tone pro-
voked by strong emotion, and can present as subtle, barely noticeable weak-
ness leading to stumbling over words or dropping things, or can be severe
enough to preclude all movement except diaphragmatic breathing and
oculomotor contractions. Cataplexy is a REM-intrusive phenomenon,
that is, an isolated component of REM sleep (in this case, loss of skeletal
muscle tone) intruding on wakefulness; other examples are sleep paralysis
(loss of skeletal muscle tone just before sleep or just after awakening) and
hypnagogic or hypnopompic hallucinations (dreaming while awake). Narco-
lepsy actually encompasses a generalized disorder of sleep–wake regulation,
such that in addition to excessive daytime sleepiness the patient may also
604 BROWN & ARORA
experience difficulty in maintaining consolidated nocturnal sleep or REM-

intrusive phenomenon during wakefulness. Major breakthroughs in our
knowledge of narcolepsy pathogenesis have occurred in the last few years,
particularly the discovery of the neurotransmitter orexin (also called hypo-
cretin) and a panoply of orexinergic circuits within the CNS that are key
components of the brain’s alerting mechanism [159]. Furthermore, loss of
these orexinergic pathways has been demonstrated to play a major role in
human and animal models of narcolepsy [160,161]. Other hypersomnias of
central origin include idiopathic hypersomnia (further differentiated by
whether normal or long sleep time is present), recurrent hypersomnia (eg,
Kleine-Levin syndrome and menstrual-related hypersomnia), and hyper-
somnias attributable to other medical conditions, drugs, or substances, or
that which is behaviorally induced by not allowing sufficient time to sleep
[30,162].
A comprehensive discussion of these disorders is beyond the scope of this
article, and the interested reader is referred elsewhere [162,163]. Because nar-
colepsy is not a particularly rare disease (prevalence in the United States is
estimated at up to 0.18%) the ICU practitioner should be cognizant of how
certain aspects of intensive care might affect the patient who has narcolepsy
[30]. For instance, abrupt discontinuation of drugs prescribed to the patient
who has narcolepsy for control of cataplexy (antidepressant medications or
g-hydroxybutyric acid, also known as sodium oxybate or GHBA) may pro-
voke a severe, sustained bout of cataplexy known as status cataplecticus
[164]. Also, certain medications potentially used in the ICU can induce
status cataplecticus, particularly a1b adrenergic antagonists (eg, prazosin)
[165], but also, theoretically, dopamine D2/3 agonists [166,167]. It can easily
be imagined that an occurrence of status cataplecticus in the ICU patient
who has narcolepsy could lead to inappropriate management of a perceived
neurologic catastrophe. Similarly, abrupt withdrawal from CNS stimulants
(eg, methylphenidate, amphetamines) or wake-promoting agents (eg,
modafinil) could lead to severe sleepiness interpreted as a change in mental
status. Finally, the intensivist should be aware of other sleep disorders that
frequently complicate narcolepsy and that could become important consid-
erations during an ICU stay. These include sleep-disordered breathing,
PLMD, and the various parasomnias [30,168].
References
[1] US Environmental Protection Agency. Information on levels of environmental noise
requisite to protect public health and welfare with an adequate margin of safety. Washing-
ton, DC: US Government Printing Office; 1974 EPA Report No. 550/9-74-004.
[2] WHO. WHO Environmental Health Criteria 12-Noise. Geneva (Switzerland): World
Health Organisation; 1980.
[3] Kahn DM, Cook TE, Carlisle CC, et al. Identification and modification of environmental
noise in an ICU setting. Chest 1998;114:535–40.
[5] Busch-Vishniac IJ, West JE, Barnhill C, et al. Noise levels in Johns Hopkins Hospital.
J Acoust Soc Am 2005;118:3629–45.
[6] Cropp AJ, Woods LA, Raney D, et al. Name that tone. The proliferation of alarms in the
intensive care unit. Chest 1994;105:1217–20.
[8] Walder B, Francioli D, Meyer J-J, et al. Effects of guidelines implementation in a surgical
intensive care unit to control nighttime light and noise levels. Crit Care Med 2000;28:
2242–7.
[9] Novaes MAFP, Knobel E, Bork AM. Stressors in ICU: perception of the patient, relatives
and health care team. Intensive Care Med 1999;25:1421–6.
[10] Simpson T, Lee ER, Cameron C. Patient’s perceptions of environmental factors that
disturb sleep after cardiac surgery. Am J Crit Care 1996;5:173–81.
[11] Cochran J, Ganong LH. A comparison of nurses’ and patients’ perceptions of intensive care
unit stressors. J Adv Nurs 1989;14:1038–43.
[12] Jones J, Hoggart B, Withey J, et al. What the patients say: a study of reactions to an inten-
sive care unit. Intensive Care Med 1979;5:89–92.
[13] Cureton-Lane RA, Fontaine DK. Sleep in the pediatric ICU: an empirical investigation.
Am J Crit Care 1997;6:56–63.
[16] Toublanc B, Rose D, Glérant J-C, et al. Assist-control ventilation vs. low levels of pressure
support ventilation on sleep quality in intubated ICU patients. Intensive Care Med 2007;33:
1148–54.
[17] Hardin KA, Seyal M, Stewart T, et al. Sleep in critically ill chemically paralyzed patients
requiring mechanical ventilation. Chest 2006;129:1468–77.
[18] Bergbom-Engberg I, Halijamae H. Assessment of patients’ experiences of discomfort
during respiratory therapy. Crit Care Med 1989;17:1068–72.
[19] Topf M, Thompson S. Interactive relationships between hospital patients’ noise-induced
stress and other stress with sleep. Heart Lung 2001;30:237–43.
[20] Bourne RS, Mills GH. Sleep disruption in critically ill patientsdpharmacological consid-
erations. Anaesthesia 2004;59:374–84.
[21] Brown WD. The effect of medication on sleep. Respir Care Clin N Am 2006;12:81–99.
[22] Pagel JF, Helfter P. Drug induced nightmaresdan etiology based review. Hum Psycho-
pharmacol 2003;18:59–67.
[23] Foldvary-Schaefer N. Sleep complaints and epilepsy: the role of seizures, antiepileptic
drugs and sleep disorders. J Clin Neurophysiol 2002;19:514–21.
[24] Reid S, Dwyer MB. Insomnia in HIV infection: a systematic review of prevalence, corre-
lates, and management. Psychosom Med 2005;67:260–9.
[25] Prosise GL, Bonnet MH, Berry RB, et al. Effects of abstinence from smoking on sleep and
daytime sleepiness. Chest 1994;105:1136–41.
Med 2001;163:451–7.
196–201.
606 BROWN & ARORA
[29] Topf M, Davis JE. Critical care unit noise and rapid eye movement (REM) sleep. Heart
Lung 1993;22:252–8.
[30] American Academy of Sleep Medicine. The international classification of sleep disorders,
diagnostic and coding manual. 2nd edition. Westchester (IL): American Academy of Sleep
Medicine; 2005.
[31] Schenck CH, Mahowald MW. Injurious sleep behavior disorders (parasomnias) affecting
patients on intensive care units. Intensive Care Med 1991;17:219–24.
[32] Jouvet M, Delorme F. Locus coeruleus et sommeil paradoxal. C R Seances Soc Biol Fil
1965;159:895–9 [in French].
[33] Lai YY, Siegel JM. Pontomedullary glutamate receptors mediating locomotion and muscle
tone suppression. J Neurosci 1991;11:2931–7.
[34] Schenck CH, Bundlie SR, Ettinger MG, et al. Chronic behavioral disorders of human REM
sleep: a new category of parasomnia. Sleep 1986;9:293–308.
[35] Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and
neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002;25:
120–38.
[36] Mahowald MW, Schenck CH, Bornemann MA. Pathophysiologic mechanisms in REM
sleep behavior disorder. Curr Neurol Neurosci Rep 2007;7:167–72.
[37] Gugger JJ, Wagner ML. Rapid eye movement sleep behavior disorder. Ann Pharmacother
2007;41:1833–41.
[38] Iranzo A, Santamaria J. Bisoprolol-induced rapid eye movement sleep behavior disorder.
Am J Med 1999;107:390–2.
[39] Betts TA, Alford C. Beta-blockers and sleep: a controlled trial. Eur J Clin Pharmacol 1985;
28(Suppl):65–8.
[40] Kostis JB, Rosen RC. Central nervous system effects of beta-adrenergic-blocking drugs: the
role of ancillary properties. Circulation 1987;75:204–12.
[41] Walder B, Tramèr MR, Blois R. The effects of two single doses of tramadol on sleep:
a randomized, cross-over trial in healthy volunteers. Eur J Anaesthesiol 2001;18:36–42.
[42] Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder
in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep
behavior disorder. Neurology 1996;46:388–93.
[43] Boeve BF, Silber MH, Ferman TJ, et al. Association of REM sleep behavior disorder and
neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;
16:622–30.
[44] Uchiyama M, Isse K, Tanaka K, et al. Incidental Lewy body disease in a patient with REM
sleep behavior disorder. Neurology 1995;45:707–12.
[45] Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degenerative
dementia: an association likely reflecting Lewy body disease. Neurology 1998;51:363–70.
[46] Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders in multiple system
atrophy. Neurology 1997;48:1094–7.
[47] Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour
disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet
Neurol 2006;5:572–7.
[48] Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demo-
graphic, clinical and laboratory findings in 93 cases. Brain 2000;123:331–9.
[49] Kunz D, Bes F. Melatonin as a therapy in REM sleep behavior disorder patients: an open-
labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov
Disord 1999;14:507–11.
[50] Takeuchi N, Uchimura N, Hashizume Y, et al. Melatonin therapy for REM sleep behavior
disorder. Psychiatry Clin Neurosci 2001;55:267–9.
[51] Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior
disorder in neurologic disorders: results in 14 patients. Sleep Med 2003;4:281–4.
[52] Fantini ML, Gagnon FF, Filipini D, et al. The effects of pramipexole in REM sleep
behavior disorder. Neurology 2003;61:1418–20.
[53] Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behavior
disorder: results from a case series. Sleep Med 2006;7:418–23.
[54] The United States Pharmacopeia. USP verified dietary supplements. Available at: http://
www.usp.org/USPVerified/dietarySupplements/supplements.html. Accessed November
26, 2007.
[55] Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology
1992;42(Suppl 6):44–52.
[56] Mahowald MW, Ettinger MG. Things that go bump in the night: the parasomnias revisited.
J Clin Neurophysiol 1990;7:119–43.
[57] Hublin C, Kaprio J, Partinen M, et al. Prevalence and genetics of sleepwalking: a popula-
tion-based twin study. Neurology 1997;48:177–8.
[58] Ohayon MM, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional
arousals in the general population: their frequency and relationship to other sleep and men-
tal disorders. J Clin Psychiatry 1999;60:268–76.
[59] Schenck CH, Milner DM, Hurwitz TD, et al. A polysomnographic and clinical report on
sleep-related injury in 100 adult patients. Am J Psychiatry 1989;146:1166–73.
[60] Lecendreux M, Bassetti C, Dauvilliers Y, et al. HLA and genetic susceptibility to sleepwalk-
ing. Mol Psychiatry 2003;8:114–7.
[61] Plazzi G, Vetrugno R, Provini F, et al. Sleepwalking and other ambulatory behaviors
during sleep. Neurol Sci 2005;26:s193–8.
[62] Laberge L, Tremblay RE, Vitaro F, et al. Development of parasomnias from childhood to
early adolescence. Pediatrics 2000;106:67–74.
[63] Hughes JR. A review of sleepwalking (somnambulism): the enigma of neurophysiology and
polysomnography with differential diagnosis of complex partial seizures. Epilepsy Behav
2007;11:483–91.
[64] Pressman MR. Disorders of arousal from sleep and violent behavior: the role of physical
contact and proximity. Sleep 2007;30:1039–47.
[65] Kavey NB, Whyte J, Resor SR Jr, et al. Somnambulism in adults. Neurology 1990;40:
749–52.
[66] Espa F, Ondze B, Deglize P, et al. Sleep architecture, slow wave activity, and sleep spindles
in adult patients with sleepwalking and sleep terrors. Clin Neurophysiol 2000;111:929–39.
[67] Pressman MR. Hypersynchronous delta sleep EEG activity and sudden arousals from
slow-wave sleep in adults without a history of parasomnias: clinical and forensic implica-
tions. Sleep 2004;27:706–10.
[68] Schenck CH, Pareja JA, Patterson AL, et al. Analysis of polysomnographic events
surrounding 252 slow-wave sleep arousals in thirty-eight adults with injurious sleepwalking
and sleep terrors. J Clin Neurophysiol 1998;15:159–66.
[69] Blatt I, Peled R, Gadoth N, et al. The value of sleep recording in evaluating somnambulism
in young adults. Electroencephalogr Clin Neurophysiol 1991;78:407–12.
[70] Gaudreau H, Joncas S, Zadra A, et al. Dynamics of slow-wave activity during the NREM
sleep of sleepwalkers and control subjects. Sleep 2000;23:755–60.
[71] Pilon M, Zadra A, Joncas S, et al. Hypersynchronous delta waves and somnambulism:
brain topography and effect of sleep deprivation. Sleep 2006;29:77–84.
[72] Joncas S, Zadra A, Paquet J, et al. The value of sleep deprivation as a diagnostic tool in
adult sleepwalkers. Neurology 2002;58:936–40.
[73] Guilleminault C, Poyares D, Aftab FA, et al. Sleep and wakefulness in somnambulism:
a spectral analysis study. J Psychosom Res 2001;51:411–6.
[74] Zadra A, Pilon M, Joncas S, et al. Analysis of postarousal EEG activity during somnam-
bulistic episodes. J Sleep Res 2004;13:279–84.
[75] Bassetti C, Vella S, Donati F, et al. SPECT during sleepwalking. Lancet 2000;356:484–5.
608 BROWN & ARORA
[76] Oliviero A, Della Marca G, Tonali PA, et al. Functional involvement of cerebral cortex in
adult sleepwalking. J Neurol 2007;254:1066–72.
[77] Hafeez ZH, Kalinowski C. Two cases of somnambulism induced by quetiapine [letter].
J Clin Psychiatry 2007;9:313.
[78] Varkey BM, Varkey LM. Topiramate nduced somnambulism and automatic behavior.
Indian J Med Sci 2003;57:508–10.
[79] Pressman MR, Mahowald MW, Schenck CH, et al. Alcohol-induced sleepwalking or
confusional arousal as a defense to criminal behavior: a review of scientific evidence,
methods and forensic considerations. J Sleep Res 2007;16:198–212.
[80] Ajlouni KM, Ahmad AT, El-Zaheri MM, et al. Sleepwalking associated with hyperthyroid-
ism. Endocr Pract 2005;11:5–10.
[81] Poryazova R, Waldvogel D, Bassetti CL. Sleepwalking in patients with Parkinson disease.
Arch Neurol 2007;64:1524–7.
[82] Espa F, Dauvilliers Y, Ondze B, et al. Arousal reactions in sleepwalking and night terrors in
adults: the role of respiratory events. Sleep 2002;25:871–5.
[83] Guilleminault C, Kirisoglu C, da Rosa AC, et al. Sleepwalking, a disorder of NREM sleep
instability. Sleep Med 2006;7:163–70.
[84] Millman RP, Kipp GJ, Carskadon MA. Sleepwalking precipitated by treatment of sleep
apnea with nasal CPAP. Chest 1991;99:750–1.
[85] Guilleminault C, Kirisoglu C, Bao G, et al. Adult chronic sleepwalking and its treatment
based on polysomnography. Brain 2005;128:1062–9.
[86] Crisp AH, Matthews BM, Oakey M, et al. Sleepwalking, night terrors, and consciousness.
BMJ 1990;300:360–2.
[87] Hartman D, Crisp AH, Sedgwick P, et al. Is there a dissociative process in sleepwalking and
night terrors? Postgrad Med J 2001;77:244–9.
[88] Szekenberger W, Niemcewicz S, Dabrowska AJ. Sleepwalking and night terrors: psycho-
logical and psychophysiological correlates. Int Rev Psychiatry 2005;17:263–70.
[89] Crisp AH. The sleepwalking/night terrors syndrome in adults. Postgrad Med J 1996;72:
599–604.
[90] Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injurious
parasomnias and other disorders of disrupted sleep in 170 adults. Am J Med 1996;100:
333–7.
[91] Balon R. Sleep terror disorder and insomnia treated with trazodone: a case report. Ann Clin
Psychiatry 1994;6:161–3.
[92] Lillywhite AR, Wilson SJ, Nutt DJ. Successful treatment of night terrors and somnambu-
lism with paroxetine. Br J Psychiatry 1994;164:551–4.
[93] Garland EJ, Smith DH. Simultaneous prepubertal onset of panic disorder, night terrors,
and somnambulism. J Am Acad Child Adolesc Psychiatry 1991;30:553–5.
[94] Cooper AJ. Treatment of coexistent night-terrors and somnambulism in adults with
imipramine and diazepam. J Clin Psychiatry 1987;48:209–10.
[95] Rundshagen I, Schnabel K, Wegner C, et al. Incidence of recall, nightmares, and hallucina-
tions during analgosedation in intensive care. Intensive Care Med 2002;28:38–43.
[96] Richman J. Coming out of intensive care crazy: dreams of affliction. Qual Health Res 2000;
10:84–102.
[97] Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress
disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 1998;26:651–9.
[98] Granja C, Lopes A, Moreira S, et al. Patients’ recollections of experiences in the intensive
care unit may affect their quality of life. Crit Care 2005;9:R96–109.
[99] Thompson DF, Pierce DR. Drug-induced nightmares. Ann Pharmacother 1999;33:93–8.
[100] Lavie P. Sleep disturbances in the wake of traumatic events. N Engl J Med 2001;345:
1825–32.
[101] Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and
disease. Part 1. Basic properties of circadian pacemakers. N Engl J Med 1983;309:469–76.
[102] Lowrey PL, Takahashi JS. Genetics of the mammalian circadian system: photic entrain-
ment, circadian pacemaker mechanisms, and posttranslational regulation. Annu Rev
Genet 2000;34:533–62.
[103] Datta S, Maclean RR. Neurobiological mechanisms for the regulation of mammalian
sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary
cellular and molecular evidence. Neurosci Biobehav Rev 2007;31:775–824.
[104] Lack LC, Wright HR. Chronobiology of sleep in humans. Cell Mol Life Sci 2007;64:
1205–15.
[105] Zisapel N. Sleep and sleep disturbances: biological basis and clinical implications. Cell Mol
Life Sci 2007;64:1174–86.
[106] Lu BS, Zee PC. Circadian rhythm sleep disorders. Chest 2006;130:1915–23.
[107] Zisapel N. Circadian rhythm sleep disorders. Pathophysiology and potential approaches to
treatment. CNS Drugs 2001;15:311–28.
[108] Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: part I, basic
principles, shift work and jet lag disorders. Sleep 2007;30:1416–83.
[109] Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: part II, advanced
sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular
sleep-wake rhythm. Sleep 2007;30:1484–501.
[110] Reinberg AE, Ashkenazi I, Smolensky MH. Euchronism, allochronism, and dyschronism:
is internal desynchronization of human circadian rhythms a sign of illness? Chronobiol Int
2007;24:553–88.
[111] Perras B, Meier M, Dodt C. Light and darkness fail to regulate melatonin release in criti-
cally ill humans. Intensive Care Med 2007;33:1954–8.
[112] Shilo L, Dagan Y, Smorjik Y, et al. Patients in the intensive care unit suffer from severe lack
of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci 1999;317:
278–81.
[113] Frisk U, Olsson J, Nylén P, et al. Low melatonin excretion during mechanical ventilation in
the intensive care unit. Clin Sci 2004;107:47–53.
[114] Olofsson K, Alling C, Lundberg D, et al. Abolished circadian rhythm of melatonin secre-
tion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand
2004;48:679–84.
[115] Shiihara Y, Nogami T, Chigira M, et al. Sleep-wake rhythm during stay in an intensive care
unit: a week’s long-term recording of skin potentials. Psychiatry Clin Neurosci 2001;55:
279–80.
[116] Segawa K, Nakazawa S, Tsukamoto Y, et al. Peptic ulcer is prevalent among shift workers.
Dig Dis Sci 1987;32:449–53.
[117] Scheen AJ, van Cauter E. The roles of time of day and sleep quality in modulating glucose
regulation: clinical implications. Horm Res 1998;49:191–201.
[118] Poole CJM, Wright AD, Nattrass M. Control of diabetes mellitus in shift workers. Br J Ind
Med 1992;49:513–5.
[119] Waclawski ER. Employment and diabetes: a survey of the prevalence of diabetic workers
known by occupational physicians, and the restrictions placed on diabetic workers in
employment. Diabet Med 1989;6:16–9.
[120] Weinhouse GL, Schwab RJ. Sleep in the critically ill patient. Sleep 2006;29:707–16.
[121] Schwab RJ. Disturbances of sleep in the intensive care unit. Crit Care Clin 1994;10:681–94.
[122] Krachman SL, D’Alonzo GE, Criner GJ. Sleep in the intensive care unit. Chest 1995;107:
1713–20.
[123] Baevsky RH, Lu MY, Smithline HA. The effectiveness of wireless telephone communica-
tion technology on ambient noise level reduction within the ED. Am J Emerg Med 2004;
22:317–8.
[124] Rashid M. A decade of adult intensive care unit design. Crit Care Nurs Q 2006;29:282–311.
[125] Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive
care patients: a pilot study. Chronobiol Int 2000;17:71–6.
610 BROWN & ARORA
[126] Ibrahim MG, Bellomo R, Hart GK, et al. A double-blind placebo-controlled randomized
study of nocturnal melatonin in tracheostomized patients. Crit Care Resusc 2006;8:187–91.
[127] Richards K, Nagel C, Markie M, et al. Use of complementary and alternative therapies to
promote sleep in critically ill patients. Crit Care Nurs Clin North Am 2003;15:329–40.
[128] Williamson JW. The effects of ocean sounds on sleep after coronary artery bypass graft
surgery. Am J Crit Care 1992;1:91–7.
[129] Stanchina ML, Abu-Hijleh M, Chaudhry BK, et al. The influence of white noise on sleep in
subjects exposed to ICU noise. Sleep Med 2005;6:423–8.
[130] Wallace CJ, Robins J, Alvord LS, et al. The effect of earplugs on sleep measures during
exposure to simulated intensive care unit noise. Am J Crit Care 1999;8:210–9.
[131] Ekbom KA. Restless legs syndrome. Neurology 1960;10:868–73.
[132] Walters AS. International restless legs study group: toward a better definition of the restless
legs syndrome. Mov Disord 1995;10:634–42.
[133] Lavigne G, Montplaisir J. Restless legs syndrome and sleep bruxism: prevalence and asso-
ciation among Canadians. Sleep 1994;17:739–43.
[134] Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs
syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms,
and treatment) primary care study. Sleep Med 2004;5:237–46.
[135] Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact.
Arch Intern Med 2005;165:1286–92.
[136] Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord 2007;22:
S440–8.
[137] Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal
disease. Am J Kidney Dis 1996;28:372–8.
[138] Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology
2004;63:1065–9.
[139] Glasauer FE. Restless legs syndrome. Spinal Cord 2001;39:125–33.
[140] Winkelmann J, Schadrack J, Wetter TC, et al. Opioid and dopamine antagonist drug
challenges in untreated restless legs syndrome patients. Sleep Med 2001;2:57–61.
[141] Allen RP, Earley CJ. Restless legs syndrome. A review of clinical and pathophysiological
features. J Clin Neurophysiol 2001;18:128–47.
[142] Brown LK, Dedrick DL, Doggett J, et al. Antidepressant medication use and restless legs
syndrome in patients presenting with insomnia. Sleep Med 2005;6:443–50.
[143] Kuzniar TJ, Silber MH. Multiple skeletal injuries resulting from uncontrolled restless legs
syndrome. J Clin Sleep Med 2007;3:60–1.
[144] Ruottinen HM, Partinen M, Hublin C, et al. An FDOPA PET study in patients with
periodic limb movement disorder and restless legs syndrome. Neurology 2000;54:502–4.
[145] Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs syndrome:
18F-dopa and 11C-raclopride PET studies. Neurology 1999;52:932–7.
[146] Ondo WG, He Y, Le WD, Rajasekaran S, et al. Clinical correlates of 6-hydroxydopamine
injections into A11 dopaminergic neurons in rats: a possible model for restless legs syn-
drome. Mov Disord 2000;15:154–8.
[147] Earley CJ, Barker PB, Horská A, et al. MRI-determined regional brain iron concentrations
in early and late-onset restless legs syndrome. Sleep Med 2006;7:459–61.
[148] Earley CJ, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with
restless legs syndrome. Neurology 2001;56:263–5.
[149] Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechoge-
nicity in restless legs syndrome. Ann Neurol 2005;58:630–4.
[150] Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs
syndrome. Mayo Clin Proc 2004;79:916–22.
[151] Hening WA, Allen RP, Earley CJ, et al. Restless Legs Syndrome Task Force of the Stan-
dards of Practice Committee of the American Academy of Sleep Medicine. An update on
the dopaminergic treatment of restless legs syndrome and periodic limb movement disor-
der. Sleep 2004;27:560–83.
[152] Homann CN, Wenzel K, Suppan K, et al. Sleep attacks in patients taking dopamine
agonists: review. BMJ 2002;324:1483–7.
[153] Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome
with gabapentin. A double-blind, cross-over study. Neurology 2002;59:1573–9.
[154] Sloand JA, Shelly MA, Feigin A, et al. A double-blind, placebo-controlled trial of intrave-
nous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney
Dis 2004;43:663–70.
[155] Hornyak M, Voderholzer U, Hohagen F, et al. Magnesium therapy for periodic leg move-
ments-related insomnia and restless legs syndrome: an open pilot study. Sleep 1998;21:
501–5.
[156] Rajaram S-S, Shanahan J, Ash C, et al. Enhanced external counter pulsation (EECP) as
a novel treatment for restless legs syndrome (RLS): a preliminary test of the vascular
neurologic hypothesis for RLS. Sleep Med 2005;6:101–6.
[157] Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;32:431–42.
[158] Chisolm T, Morehouse RL. Adult headbanging: sleep studies and treatment. Sleep 1996;19:
343–6.
[159] Eggermann E, Serafin M, Bayer L, et al. Orexins/hypocretins excite basal forebrain cholin-
ergic neurons. Neuroscience 2001;108:177–81.
[160] Nishino S. The hypothalamic peptidergic system, hypocretin/orexin and vigilance control.
Neuropeptides 2007;41:117–33.
[161] Siegel JM, Boehmer LN. Narcolepsy and the hypocretin systemdwhere motion meets
emotion. Nat Clin Pract Neurol 2006;2:548–56.
[162] Young TJ, Silber MH. Hypersomnias of central origin. Chest 2006;130:913–20.
[163] Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med 2007;8:373–99.
[164] Martı́nez-Rodrı́guez J, Iranzo A, Santamarı́a J, et al. Status cataplecticus induced by
abrupt withdrawal of clomipramine. Neurologia 2002;17:113–6.
[165] Aldrich MS, Rogers AE. Exacerbation of human cataplexy by prazosin. Sleep 1989;12:
254–6.
[166] Honda K, Riehl J, Mignot E, et al. Dopamine D3 agonists in the substantia nigra aggravate
cataplexy but do not modify sleep. Neuroreport 1999;10:3717–24.
[167] Okura M, Fujiki N, Kita I, et al. The roles of midbrain and diencephalic dopamine cell
groups in the regulation of cataplexy in narcoleptic Dobermans. Neurobiol Dis 2004;16:
274–82.
[168] Chakravorty SS, Rye DB. Narcolepsy in the older adult: epidemiology, diagnosis and
management. Drugs Aging 2003;20:361–76.
Crit Care Clin 24 (2008) 613–626
The Sleep-Friendly ICU

Aharon E. Sareli, MD*, Richard J. Schwab, MD
Division of Sleep Medicine and Division of Pulmonary, Allergy and Critical Care
University of Pennsylvania, 3624 Market Street, Suite 205, Philadelphia, PA 19141, USA
Achieving restorative sleep in the ICU remains a challenge for most

patients. Multiple environmental and nonenvironmental factors interact to
affect sleep and cause disruption to normal sleep patterns.
There are many hurdles that need to be overcome to improve sleep pat-
terns in the critically ill patient. By definition, the patients in the ICU have
the highest severity of illness of all hospitalized patients. Providing maximal
medical attention in the context of minimal interruptions (intended to facil-
itate restorative sleep) seems to be paradoxical in intent.
Furthermore, physicians and allied medical personnel do not always
appreciate the lack of adequate sleep that patients achieve in the ICU. When
compared with objective polysomnogram data (used to determine total patient
sleep time in the ICU) medical personnel’s estimation of sleep time is shown to
be inflated [1]. A nihilistic approach to facilitating restful sleep in ICUs is coun-
terproductive. Although many factors that impact sleep in the ICU are not
modifiable, others can be targeted in a constructive manner. As with any aspect
of medical care whose impact is underappreciated, an initial step of raising
awareness and appreciation of the scope of the problem is crucial.
A substantial volume of published study data illustrates that sleep architec-
ture is disrupted in critically ill patients. Importantly, critically ill patients are
aware of their disrupted sleep patterns and find poor sleep to be extremely dis-
tressing [2–6]. In contrast, few data exist to investigate the consequences of
poor sleep on patient morbidity, mortality, and quality-of-life outcomes after
hospital discharge. One reason to explain this seeming discrepancy is that sep-
aration of the impact of sleep architecture from the multitude of confounding
variables that are associated with sleep disturbance is a daunting task. Never-
theless, an understanding of the full impact of disrupted sleep architecture in
critically ill patients is needed. Until such data become available, creating
E-mail address: aharon.sareli@uphs.upenn.edu (A.E. Sareli).
614 SARELI & SCHWAB
a sleep-friendly ICU aimed at reducing patients’ discomfort and perceived

burden of illness remains an independent worthy goal.
Altered sleep patterns in the ICU

Normal sleep architecture is categorized into non–rapid eye movement
(REM; stages 1, 2, 3 and 4) and REM sleep (rapid eye movements, muscle
atonia, and dreaming). Sleep stages are defined on the basis of electroen-
cephalographic (EEG) patterns. Stages 3 and 4 represent slow-wave sleep
(delta waves) as compared with stage 1 (low voltage fast EEG with slow roll-
ing eye movements) and stage 2 (spindles and K complexes) (see figures in
the article by Dr. Collop titled, ‘‘Normal Sleep and Circadian Processes’’
for examples of normal sleep EEG patterns, elsewhere in this issue). Both
REM sleep and slow-wave sleep are considered crucial to restorative sleep.
For restorative sleep to be achieved, not only is an adequate total sleep time
required but also a normal distribution of sleep stages (in particular REM
and slow-wave sleep).
Normal sleep architecture varies with age and among individuals. The fol-
lowing distribution of sleep stages can be considered to represent a ‘‘normal’’
healthy young adult: 2% to 5% stage 1, 45% to 55% stage 2, 3% to 8% stage
3, 10% to 15% stage 4, and 20% to 25% REM [7]. Normal healthy adults
transition from wake to sleep in approximately 10 to 20 minutes (sleep onset
latency) and the first REM period occurs within 90 to 120 minutes of sleep
onset. A polysomnogram consists of a recording of multiple EEG tracings
and other parameters, such as oxygen saturation, respiratory rate, and effort,
along with oral and nasal airflow. It is the best current available tool that
provides objective data regarding sleep architecture and sleep patterns.
Total sleep time per 24-hour period in an ICU is similar to that of non-
hospitalized patients but marked differences exist in the sleep architecture
itself [8–12]. As much as half of a critically ill patient’s sleep occurs during
daylight hours. Stages 1 and 2 of sleep typically represent a larger percent-
age of total sleep time as compared with nonhospitalized patients. In con-
trast, the duration of stages 3 and 4 (slow-wave sleep) are reduced as is
the percentage of REM sleep time (fewer REM periods and shorter dura-
tion). Frequent arousals and subsequent sleep fragmentation are common
in the ICU patient (Figs. 1 and 2). Altered patterns of sleep noted during
ICU stay may take days to normalize and persist even after patient is trans-
ferred out of the ICU [9].
Physiologic consequences of sleep deprivation

Although there are few data to directly link the consequences of altered
sleep patterns in the ICU to increased patient morbidity or mortality, it is
important to recognize the physiologic consequences of poor sleep. The
THE SLEEP-FRIENDLY ICU 615
Fig. 1. Polysomnogram from a patient in an ICU depicting an EEG arousal following a burst
of noise. (Adapted from Freedman NS, Gazendam J, Levan L, et al. Abnormal sleep/wake
cycles and the effect of environmental noise on sleep disruption in the intensive care unit.
Am J Respir Crit Care Med 2001;163:451–7; with permission.)
absence of such data may reflect the difficulties of appropriate clinical trial
design rather than an absence of an impact of sleep disruption on patient
morbidity and mortality.
Sleep serves a pivotal role in maintaining normal biologic equilibrium
and function. Sleep patterns are known to affect immune function, hor-
monal function, catecholamines levels, pathways of metabolism, pulmonary
mechanics, control of breathing, and neurocognitive function.
Fig. 2. Fragmented bouts of sleep in five critically ill patients. (Adapted from Freedman NS,
Gazendam J, Levan L, et al. Abnormal sleep/wake cycles and the effect of environmental noise
on sleep disruption in the intensive care unit. Am J Respir Crit Care Med 2001;163:451–7; with
permission.)
616 SARELI & SCHWAB
Immune function
Despite controversy, the notion that sleep loss leads to impaired defense
mechanisms and renders an individual more susceptible to infection has
gained increasing acceptance [13–15]. Various authors have documented
a modulation of immune function relative to sleep patterns; the changes de-
scribed are primarily related to T cell–mediated immunity and interleukin
levels [16–20]. The changes in the immune system are robust but their impact
on the ability to recover from illness or to increase susceptibility to illness is
not directly proven. Irwin and colleagues [16] studied a group of healthy hu-
man volunteers after a single night of moderate sleep deprivation (10 PM to
3 AM). A reduction of natural immune responses was noted as measured by
decreased natural killer cell number and cytotoxicity and a decrease in lym-
phokine-activated killer cell number and activity. Interleukin 2 production
was also suppressed in these subjects. Benedict and colleagues [18] provide
data that interleukin 7 levels are increased during sleep in humans. IL7 facil-
itates the transition of CD8þ effector to memory T cells and lengthens sur-
vival of the T-cell memory cells [20]. In another study, adult patients who
were sleep deprived exhibited impaired response to influenza vaccination [17].
The most striking animal study illustrating an impaired immune system
following sleep deprivation describes an increased rate of bacteremia in
rats chronically deprived of sleep. Bacteremia was present in five of the
six rats that were subjected to sustained sleep deprivation [21]. Animal
models involving sleep deprivation manifest other changes in immune func-
tion. Data obtained in rats that were sleep deprived for 96 hours revealed
increased complement C3 in relation to the control group. In the same
study, rats that were sleep restricted for 21 days exhibited decreased spleen
weight, total leukocytes, and lymphocytes, but increased levels of IgM when
compared with the control group [13]. Bergmann and colleagues [22] dem-
onstrated a decrease in tumor growth rate of sleep-deprived rats, illustrating
another potential facet in the manner that immune function may be affected
by sleep patterns.
In summary, various changes involving the immune system occur during
sleep and moreover immune modulation has been documented in subjects
who manifest sleep deprivation. There is little doubt that sleep plays an im-
portant role in maintaining immune function. More data are needed, how-
ever, to comprehensively describe the scope of changes in the immune
system during sleep and in addition to link sleep deprivation directly to pa-
tient morbidity and mortality.
Hormonal systems and metabolism

Sleep deprivation results in extensive changes to homeostatic mechanisms
and markedly affects neuroendocrine stress systems. Animal models of sleep
deprivation in rats have shown reductions in body temperature and weight
despite increased energy expenditure. In addition, the same model evidenced
changes in thyroid hormone metabolism and catecholamine levels [23].

Schmid and colleagues [24] evaluated the impact of one night of sleep dep-
rivation in healthy men on basal morning secretory activity of glucose reg-
ulatory neuroendocrine systems and on the counterregulatory hormonal
response to hypoglycemia. Significant decreases in basal glucagon were
noted after one night of sleep deprivation along with other changes in glu-
cose hormonal regulation. Spiegel and colleagues [25] documented the
effects of sleep debt on carbohydrate metabolism, thyrotropic function,
and activity of the hypothalamo-pituitary-adrenal axis in healthy males.
Subjects showed decreased glucose tolerance, lower thyrotropin levels, and
elevated evening cortisol when compared with a fully rested state. The im-
pact of sleep deprivation on glucose metabolism is of great importance, in
light of data showing an impact on patient morbidity and mortality in select
ICU populations [26,27]. In an important single-center study involving 1548
surgical patients in intensive care, Van den Berghe and colleagues [26]
showed a morbidity and mortality advantage using tight glycemic control
parameters. Other studies have supported using tight glycemic control in
critically ill patients; however, the risk for hypoglycemic episodes and opti-
mal glucose levels require further definition [28–30]. In addition to the effect
of sleep deprivation on glucose metabolism, sleep deprivation has also been
shown to affect thyroid hormone homeostatic pathways. Parker and col-
leagues [31] demonstrated significant alteration of the daily TSH waveform
after severe sleep deprivation lasting 64 hours.
In summary, sleep deprivation causes increased thyroid hormone, norepi-
nephrine, and cortisol levels and decreased growth hormone levels and insu-
lin resistance. Glycemic control in the ICU has been shown to affect patient
morbidity and mortality. Nonetheless, the effect of sleep disruption in an
ICU setting on hormonal levels and homeostasis needs further study.
Control of breathing and pulmonary mechanics

Spengler and colleagues [32] demonstrated that sleep deprivation in a con-
trolled laboratory environment does not reduce the sensitivity of central
chemoreceptors or affect resting ventilation or metabolism. These data con-
trast with previous studies that suggested that the ventilatory response to
hypercapnia and hypoxemia was reduced after sleep deprivation [33,34].
These studies were performed in healthy volunteers, however, and may
not apply to the critically ill population, which is characterized by a unique
pattern of sleep disturbance rather than continuous sleep deprivation.
Schiffman and colleagues [34] studied healthy, non-obese volunteers and
found that 24 hours of sleep deprivation had no effect on spirometry results.
Chen and Tang [35] conducted a study in healthy volunteers to evaluate the
effect of sleep deprivation on respiratory muscle function. After 30 hours of
sleep deprivation inspiratory muscle endurance was reduced (as evidenced
by a reduced product of inspiratory muscle load and sustained time),
618 SARELI & SCHWAB
whereas FEV1 and FVC were unaltered. No data exist to explore the effect
of sleep deprivation on respiratory muscle function of critically ill patients
and more importantly on mechanically ventilated patients. It is possible
that by reducing respiratory muscle endurance or compromising pulmonary
function sleep disruption may hamper the ability of mechanically ventilated
patients to be successfully weaned.
Neurocognition
Delirium is highly prevalent in ICUs [36]. It is defined as a state of acute
confusion and associated cognitive impairment with fluctuating mental sta-
tus. In a large prospective study of consecutive patients admitted to ICU for
more than 24 hours, Ouimet and colleagues [36] describe an incidence of
delirium of 31.8%. Other studies describe incidences of delirium ranging
from 11% to more than 80% [36–42]. Furthermore, there is a substantial
body of evidence that demonstrates an increased risk for death, longer hos-
pital length of stay, and increased costs with delirium [36–38,43–45]. There
are many cognitive consequences of sleep loss that are similarly found in the
delirious state. In healthy volunteers sleep deprivation has been shown to
impair response time, attention, memory, and other aspects of cognitive
function [46,47]. The link between sleep deprivation and delirium in the
ICU is currently unproven. Nevertheless, as sleep deprivation clearly affects
cognitive function it is reasonable to suspect the existence of a relationship
between delirium and sleep deprivation in critically ill patients.
Factors that affect sleep in the ICU

A complex relationship exists between the multitude of factors that affect
sleep in the ICU (Box 1). Some factors are modifiable, whereas others are
inherent to the patient, his or her disease status, and variable responses to
stress. There are extremely few data concerning the direct effects of critical
illness itself on sleep. Factors such as hypotension, hypoxemia (sustained or
intermittent), hypercapnia, variable airway pressures, and endotoxin/
sepsis are but a few of the conditions that theoretically may affect sleep
[48–51]. In addition, although it seems logical that certain individuals (or
those who have certain disease states) may be more susceptible or prone
to factors in the ICU that disrupt sleep, no data exist to support or quantify
this premise.
Modifiable environmental factors include ambient noise, ambient light,
equipment alarms, and procedures. Modifiable patient factors may include
mechanical ventilation (in its various modes) and medications used for seda-
tion and analgesia. In the past, ambient noise and light were believed to rep-
resent the greatest disruption to restorative sleep in the ICU. Recent data
reveal that ambient noise and light account for only a small fraction of sleep
arousals and awakenings [50,52,53]. Guidelines aimed at ambient noise and
Box 1. Factors affecting sleep in the ICU

Patient factors
Underlying medical illness, including existing sleep disturbance
(sleep apnea, periodic limb movements, narcolepsy)
Current illness (severity of illness)
Treatment of current illness
Medications and side effects
Need for and mode of mechanical ventilation
Pain
Anxiety
Agitation
Environment factors
Ambient light
Ambient noise
Equipment (television, ventilator, monitoring equipment)
Alarms (ventilator, telemetry, oximetry)
Procedures (blood draws, electrocardiograms, radiologic studies)
Nursing: bathing, cleaning, monitoring, vital signs, medication
administration
Beepers, conversation
light reduction in the ICU have been shown to effectively decrease these
modifiable environmental factors [53]. Ambient noise and light reduction in-
terventions have not been shown to improve sleep in ICU patients based on
polysomnogram data, however. Guidelines that target specific modifiable fac-
tors fail to recognize a potential synergy attributable to multiple simultaneous
interventions. A strategy aimed at concurrent reduction of noise, ambient
light, and patient interruptions may be far more effective than individually
targeting isolated parameters. An integrative strategy is neededdone that tar-
gets modifiable environmental and patient factors and uses polysomnogram
data to objectively measure sleep.
Noise
The World Health Organization has recognized the impact of noise on
health and in particular the effect of noise levels in hospitals (and in the
ICU). Although the decibel (dB) scale is linear, it reflects logarithmic in-
creases in perceived sound. An increase in 10 dB therefore represents a dou-
bling of perceived sound levels [54]. Various reference points are necessary
to best appreciate the relevant noise levels in the ICU. A sound level of
20 dB represents the equivalent of a soft whisper. Levels from 60 dB to
70 dB are sound levels typical of a busy office or laboratory with operating
620 SARELI & SCHWAB
equipment and 85 dB would be the equivalent of pneumatic tube arrival

[50,54]. The US Environmental Protection Agency (EPA) recommends hos-
pital noise levels to be no greater than 35 dB during the night and 45 dB dur-
ing the day [55]. Multiple studies have indicated that although noise levels in
ICUs vary, these recommended levels are often exceeded [50,52,53,56]. Peak
noise levels in ICU settings have been shown to be as high as 60 dB to 84 dB
[56,57]. Christensen [58] described background noise in a nine-bed, open-
plan ICU to be in excess of 50 dB both during the day and during the night,
with concurrent noise spikes exceeding 70 dB. Investigators have attempted
to tease out the relative significance of background noise as compared with
noise spikes (deviation from background levels) but no conclusive data exist
as to which of these factors is most disruptive to sleep in the ICU [52,59].
Elevated background noise levels and noise spikes contribute to arousals
and awakenings from sleep in the ICU.
Freedman and colleagues [50] studied 22 patients in a medical ICU, 20 of
whom were mechanically ventilated. Polysomnography and environmental
noise measurements were recorded for 24 to 48 hours. Environmental noise
was only responsible for 11.5% of all arousals and 17% of all awakenings
from sleep [50]. In a subsequent study by Gabor and colleagues [52], noise
levels and noise sources were collected in an open ICU environment. In
this study, healthy volunteers were studied in closed single-bed rooms in
the ICU. Noise levels had a different impact on the healthy subjects than
on the critically ill patients. In critically ill patients, arousals attributable
to sound accounted for 17.5% of all arousals and awakenings attributable
to sound accounted for 24% of all awakenings. Sound from talking and
ICU activities caused a higher number of arousals and awakenings than
did noise from alarms. In the healthy volunteers, noise levels accounted
for a far greater percentage of arousals and awakenings. This finding sug-
gests that ICU patients may acclimate to the effects of noise on sleep.
Multiple unanswered questions remain regarding the importance of back-
ground noise levels, peak noise levels, and their impact on sleep disruption
in the ICU. Several conclusions can be drawn considering the current avail-
able evidence. Noise levels in ICUs exceed current recommended guidelines
by the EPA. Although most patient arousals in the ICU are not linked to
noise levels [50,52], noise levels do contribute to arousals and awakenings
and thereby fragment sleep in critically ill patients. In addition, noise may
prevent ICU patients from falling asleep. The use of earplugs has been iden-
tified as a practical intervention that is comfortable and acceptable to pa-
tients in intensive care [60–62].
Noise represents a modifiable factor that can impact patients’ sleep pat-
terns in the ICU. Further studies are needed to explore the effect of noise
reduction on patients’ sleep patterns in the ICU environment. Such studies
should aim to reduce noise levels and correlate reduced noise levels with pol-
ysomnogram data. The impact of noise reduction on the sleep patterns of
healthy volunteers may be far different from that on critically ill patients.
Light levels
Light is essential as a synchronizer for the circadian clock. Levels as low
as 100 to 180 lux (equivalent of dim room light) can affect the circadian
pacemaker [63,64]. Consequently it is plausible that variations in light levels
affect sleep patterns in critically ill patients.
Patients surveyed after critical care illness did not find light as disruptive
to sleep patterns when compared with noise levels [5]. Meyer and colleagues
[56] recorded light levels in different hospital locations on a minute-by-
minute interval over a 7-day period. Light levels varied in peak intensity
and distribution in a medical ICU, respiratory care ICU (single-bed room
and multiple-bed rooms), and private rooms. Light intensity levels in the
respiratory care unit followed a circadian pattern and ranged from 318.5
to 4958 lux. Other studies have described nocturnal ICU light levels as
low as 5 lux [56]. No studies have correlated light exposure with polysomno-
gram data, however. It is possible that bursts of light from adjoining rooms
and sudden light exposures may cause patient arousals and awakenings A
study by Walder and colleagues [53] explored interventions aimed at reduc-
ing light and noise levels in an ICU; however, the impact of this intervention
on polysomnogram patterns was not assessed.
Prior studies document the variability of light level intensity at various
times and locations in hospitals. Interventions to modify patients’ light
exposure are possible. Currently no data exist to document the effect of
modification of ambient light exposure on patients’ sleep architecture using
polysomnogram data. It is interesting that light is not perceived by patients
to be a major disrupter of sleep [5]; however, important differences may exist
between a patient’s perception and objective polysomnogram data.
Other factors
In trying to identify causes for patient arousals and awakenings, Gabor and
colleagues [52] found that only 10% of arousals were related to patient care ac-
tivities, approximately 20% to noise, and the cause of 68% of the arousals and
awakenings was unknown. Freedman and colleagues [5] explored patients’ per-
ceptions of the causes of sleep disruption in the ICU by using questionnaires.
Interestingly, the recording of vital signs (rather than noise and light) was found
to be the major perceived cause of sleep disruption. Although patient percep-
tion is certainly important, differences may exist when perception is compared
with polysomnogram data. It is likely that the cause for most patient arousals
and awakening are multifactorial, with contributions from environmental and
nonenvironmental factors. Further investigation in this area is needed.
Medications in the ICU

Many patients treated in the ICU need pain management. Additionally,
sedation is often required to maintain patient comfort and safety. Although
622 SARELI & SCHWAB
drugs used to achieve analgesia and sedation often have hypnotic function,
they are not used primarily for hypnotic purposes. Current recommenda-
tions by the society of critical care medicine offer guidelines for the sustained
use of sedatives and analgesics in the critically ill adult [65]. Nonpharmaco-
logic measures and optimization of the environment are recommended in
addition to using hypnotics as adjuncts to facilitate restorative sleep (grade
B recommendation) [65].
Emerging data suggest that inadequate sleep may contribute to the devel-
opment of delirium in the ICU and thereby affect patient morbidity and
mortality. Certain patterns of sedative and analgesic use (specifically benzo-
diazepines, meperidine, and opiates) likely contribute to the development of
delirium [66].
Opiates, benzodiazepines, and medications with anticholinergic action
(such as tricyclic antidepressants and antihistamines) act to suppress
REM. Opiates and benzodiazepines also suppress slow-wave sleep. Multiple
drugs that are often used in the ICU for indications other than sedation and
analgesia affect and disrupt sleep patterns in various different ways [66–68].
In summary, although many questions remain unanswered, it seems that
there is an association between sleep and delirium in the ICU. The develop-
ment of delirium in the ICU can be linked to commonly used analgesics and
sedatives. Last and perhaps most important, the development of delirium in
the ICU affects patient morbidity and mortality.
Summary
Despite large gaps in our current knowledge, mounting evidence suggests
an interaction between sleep, delirium, and morbidity and mortality in the
ICU. The nature of the interaction is complex and difficult to clearly define.
Attempting to tease out the relative importance of restorative sleep, within
the framework of critically ill patients, multiple comorbidities, and poly-
pharmacy, remains a difficult challenge. Physicians and allied medical per-
sonnel should be aware of the potential importance of restorative sleep
and its impact on the critically ill patient’s well being.
Based on current available data, nonpharmacologic efforts to maintain
a quiet environment and eliminate unnecessary patient interruptions seem
logical. The use of benzodiazepines and narcotics, aimed at providing anal-
gesia and ensuring patient safety, need close monitoring and adjustment to
the lowest effective dosages. Cautious monitoring for the onset of delirium
with the use of opiates and benzodiazepines is warranted. The use of newer
hypnotic agents, such as zolpidem and ramelteon, need to be explored in
the ICU setting. Inherent differences from the benzodiazepine class may
prove these agents to be suitable for the ICU environment. Medications
with anticholinergic effects (such as Benadryl), intended primarily as hyp-
notics, should be avoided. It is crucial to bear in mind the heterogenous
nature of the ICU population. Mechanically ventilated patients, who require
sedation for the purposes of optimal ventilation, likely represent a unique

subgroup. This subgroup may differ dramatically in sleep target goals and
optimal hypnotic medications when compared with the nonventilated pa-
tients in the ICU.
At present, no data exist to directly link patient morbidity and mortality
to sleep disruption in the critical care setting. Rather, a vast body of data
exists that suggests an impact of sleep patterns on immune mechanisms, re-
spiratory function, hormonal homeostasis, and neurocognition. Further-
more, disrupted sleep in the critical care setting is perceived by patients to
be extremely distressing. Until such time that the impact of disrupted sleep
in the critical care setting is better explained, it is appropriate to attempt to
provide patients with consolidated, restorative sleep if this can be safely
achieved.
With more clinical trials and new data, the true meaning of a sleep-
friendly ICU should become better defined.
References
recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed)
1985;290:1029–32.
[2] Novaes MA, Knobel E, Bork AM, et al. Stressors in ICU: perception of the patient, relatives
and health care team. Intensive Care Med 1999;25:1421–6.
[3] Rotondi AJ, Chelluri L, Sirio C, et al. Patients’ recollections of stressful experiences while
receiving prolonged mechanical ventilation in an intensive care unit. Crit Care Med 2002;
30:746–52.
[4] Nelson JE, Meier DE, Oei EJ, et al. Self-reported symptom experience of critically ill cancer
patients receiving intensive care. Crit Care Med 2001;29:277–82.
[6] Simini B. Patients’ perceptions of intensive care. Lancet 1999;354:571–2.
[7] Carskadon MA, Dement WC. In: Kryger MH, Roth T, Dement WC, editors. Principles and
practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 13–23.
[9] Richards KC, Bairnsfather L. A description of night sleep patterns in the critical care unit.
Heart Lung 1988;17:35–42.
196–201.
[12] Hilton BA. Quantity and quality of patients’ sleep and sleep-disturbing factors in a respira-
tory intensive care unit. J Adv Nurs 1976;1:453–68.
[13] Zager A, Andersen ML, Ruiz FS, et al. Effects of acute and chronic sleep loss on immune
modulation of rats. Am J Physiol Regul Integr Comp Physiol 2007;293:R504–9.
[14] Krueger JM, Karnovsky ML. Sleep as a neuroimmune phenomenon: a brief historical
perspective. Adv Neuroimmunol 1995;5:5–12.
[15] Krueger JM, Majde JA. Sleep as a host defense: its regulation by microbial products and
cytokines. Clin Immunol Immunopathol 1990;57:188–99.
624 SARELI & SCHWAB
[16] Irwin M, McClintick J, Costlow C, et al. Partial night sleep deprivation reduces natural killer
and cellular immune responses in humans. FASEB J 1996;10:643–53.
[17] Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immuniza-
tion. JAMA 2002;288:1471–2.
[18] Benedict C, Dimitrov S, Marshall L, et al. Sleep enhances serum interleukin-7 concentrations
in humans. Brain Behav Immun 2007;21:1058–62.
[19] Born J, Lange T, Hansen K, et al. Effects of sleep and circadian rhythm on human circulating
immune cells. J Immunol 1997;158:4454–64.
[20] Kaech SM, Tan JT, Wherry EJ, et al. Selective expression of the interleukin 7 receptor
identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol
2003;4:1191–8.
[21] Everson CA. Sustained sleep deprivation impairs host defense. Am J Physiol 1993;265:
R1148–54.
[22] Bergmann BM, Rechtschaffen A, Gilliland MA, et al. Effect of extended sleep deprivation on
tumor growth in rats. Am J Physiol 1996;271:R1460–4.
[23] Bergmann BM, Everson CA, Kushida CA, et al. Sleep deprivation in the rat: V. Energy use
and mediation. Sleep 1989;12:31–41.
[24] Schmid SM, Hallschmid M, Jauch-Chara K, et al. Sleep loss alters basal metabolic hormone
secretion and modulates the dynamic counterregulatory response to hypoglycemia. J Clin
Endocrinol Metab 2007;92:3044–51.
[25] Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine
function. Lancet 1999;354:1435–9.
[26] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill
patients. N Engl J Med 2001;345:1359–67.
[27] Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin ther-
apy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–66.
[28] Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical
ICU. N Engl J Med 2006;354:449–61.
[29] Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/
surgical intensive care units: benefit versus harm. Diabetes 2006;55:3151–9.
[30] Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically
ill adult patients. Mayo Clin Proc 2004;79:992–1000.
[31] Parker DC, Rossman LG, Pekary AE, et al. Effect of 64-hour sleep deprivation on the
circadian waveform of thyrotropin (TSH): further evidence of sleep-related inhibition of
TSH release. J Clin Endocrinol Metab 1987;64:157–61.
[32] Spengler CM, Shea SA. Sleep deprivation per se does not decrease the hypercapnic ventila-
tory response in humans. Am J Respir Crit Care Med 2000;161:1124–8.
[33] White DP, Douglas NJ, Pickett CK, et al. Sleep deprivation and the control of ventilation.
[34] Schiffman PL, Trontell MC, Mazar MF, et al. Sleep deprivation decreases ventilatory
response to CO2 but not load compensation. Chest 1983;84:695–8.
[35] Chen HI, Tang YR. Sleep loss impairs inspiratory muscle endurance. Am Rev Respir Dis
1989;140:907–9.
[36] Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence, risk factors and consequences of
ICU delirium. Intensive Care Med 2007;33:66–73.
[37] Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically
ventilated patients in the intensive care unit. JAMA 2004;291:1753–62.
[38] Lin SM, Liu CY, Wang CH, et al. The impact of delirium on the survival of mechanically
ventilated patients. Crit Care Med 2004;32:2254–9.
[39] Kishi Y, Iwasaki Y, Takezawa K, et al. Delirium in critical care unit patients admitted
through an emergency room. Gen Hosp Psychiatry 1995;17:371–9.
[40] McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and
clinical course in older patients. J Am Geriatr Soc 2003;51:591–8.
[41] Aldemir M, Ozen S, Kara IH, et al. Predisposing factors for delirium in the surgical intensive
care unit. Crit Care 2001;5:265–70.
[42] Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium. A review of 80 primary data-
collection studies. Arch Intern Med 1995;155:461–5.
[43] Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically
ventilated patients. Crit Care Med 2004;32:955–62.
[44] Edelstein DM, Aharonoff GB, Karp A, et al. Effect of postoperative delirium on outcome
after hip fracture. Clinical Orthopaedics and Related Research 2004;422:195–200.
[45] Thomason JW, Shintani A, Peterson JF, et al. Intensive care unit delirium is an independent
predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit
Care 2005;9:R375–81.
[46] Harrison Y, Horne JA, Rothwell A. Prefrontal neuropsychological effects of sleep depriva-
tion in young adultsda model for healthy aging? Sleep 2000;23:1067–73.
[47] Dinges DF, Pack F, Williams K, et al. Cumulative sleepiness, mood disturbance, and
psychomotor vigilance performance decrements during a week of sleep restricted to
4–5 hours per night. Sleep 1997;20:267–77.
[48] Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal
from sleep. Am Rev Respir Dis 1990;142:295–300.
[49] Preas HL II, Jubran A, Vandivier RW, et al. Effect of endotoxin on ventilation and breath
variability: role of cyclooxygenase pathway. Am J Respir Crit Care Med 2001;164:620–6.
Med 2001;163:451–7.
[51] Mundigler G, Delle-Karth G, Koreny M, et al. Impaired circadian rhythm of melatonin
secretion in sedated critically ill patients with severe sepsis. Crit Care Med 2002;30:536–40.
[53] Walder B, Francioli D, Meyer JJ, et al. Effects of guidelines implementation in a surgical
intensive care unit to control nighttime light and noise levels. Crit Care Med 2000;28:2242–7.
[54] Grumet GW. Pandemonium in the modern hospital. N Engl J Med 1993;328:433–7.
[55] US EPA 1974. Report no. 550-9-74-004. Information on levels of environmental noise
requisite to protect public health and welfare with an adequate margin of safety. Washing-
ton, DC: U.S. Government Printing Office, 550-9-74-004; 1974.
[57] Bentley S, Murphy F, Dudley H. Perceived noise in surgical wards and an intensive care area:
an objective analysis. Br Med J 1977;2:1503–6.
[58] Christensen M. Noise levels in a general intensive care unit: a descriptive study. Crit Care
Nurse 2007;12:188–97.
[59] Stanchina ML, Abu-Hijleh M, Chaudhry BK, et al. The influence of white noise on sleep in
subjects exposed to ICU noise. Sleep Med 2005;6:423–8.
[60] Wallace CJ, Robins J, Alvord LS, et al. The effect of earplugs on sleep measures during
exposure to simulated intensive care unit noise. Am J Crit Care 1999;8:210–9.
[61] Haddock J. Reducing the effects of noise in hospital. Nurs Stand 1994;8:25–8.
[62] Richardson A, Allsop M, Coghill E, et al. Earplugs and eye masks: do they improve critical
care patients’ sleep? Nurs Crit Care 2007;12:278–86.
[63] Boivin DB, Duffy JF, Kronauer RE, et al. Dose-response relationships for resetting of
human circadian clock by light. Nature 1996;379:540–2.
[64] Zeitzer JM, Dijk DJ, Kronauer R, et al. Sensitivity of the human circadian pacemaker to
nocturnal light: melatonin phase resetting and suppression. J Physiol 2000;526:695–702.
[65] Jacobi J, Fraser GL, Coursin DB, et al. Task force of the American College of Critical Care
Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of
626 SARELI & SCHWAB
Health-system Pharmacists (ASHP), American College of Chest Physicians. Clinical practice

guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care
Med 2002;30:119–41.
[66] Bourne RS, Mills GH. Sleep disruption in critically ill patientsdpharmacological consider-
ations. Anaesthesia 2004;59:374–84.
[67] Pandharipande P, Ely EW. Sedative and analgesic medications: risk factors for delirium and
sleep disturbances in the critically ill. Crit Care Clin 2006;22:313–27.
[68] Weinhouse GL, Schwab RJ. Sleep in the critically ill patient. Sleep 2006;29:707–16.

Critical Care Cli

Caricato da

Informazioni sul documento

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Critical Care Cli

Caricato da

Copyright:

Formati disponibili

Crit Care Clin 24 (2008) xiii

Sleep is a basic physiologic function of the human body. It is required to

obesity-hypoventilation syndrome, the overlap syndrome (patients who

Normal Sleep and Circadian Processes

Sleep is a natural process occurring in animals and human beings. It is

Normal sleep staging

* Corresponding author. Division of Pulmonary/Critical Care Medicine, 1830 East

using electroencephalographic (EEG) monitoring. Sleep stage 1 (N1) com-

Sleep-wake cycles: a delicate symphony

homeostatic sleep drive is directly determined by the duration of wakeful-

Box 1. Tonic and phasic REM characteristics

Neurophysiologic centers essential to sleep-wake cycles: overivew

NORMAL SLEEP AND CIRCADIAN PROCESSES

Sleep-wake cycles over the lifespan

Physiologic changes during sleep

arrhythmia, with coupling of respiratory variation. During inspiration,

resistance causes the reduction in minute ventilation [19]. Additionally, neu-

Adverse Eﬀects of Sleep Deprivation

The hospital is not conducive to sleep. Patients commonly recount ma-

discusses the following issues essential to understanding the factors associ-

Baseline sleep history of the ICU patient

Sleep and pain

Primary sleep disorders

Impact of the ICU environment on sleep: iatrogenic environmental

Synchronous audio, video, and polysomnographic recording in seven venti-

Respiration and ventilated ICU patients

Systematic look at the impact of sleep loss on the ICU patient

Impact on the cardiovascular system

Relationship of sleep deprivation and nightmares to delirium

Relationship of circadian rhythm disturbance to delirium

and wake. The sleep–wake pattern is temporally disorganized so that sleep

Impact on metabolic/endocrine function

have negative eﬀects on glucose metabolism and to enhance variables asso-

Impact on immune function

a patient’s overall health. Poor sleep can be deleterious to patient outcome

Pharmacology I: Eﬀects on Sleep

E-mail address: gweinhouse@partners.org

lead to a burst-suppression pattern [20–22]. Both medications are also

management of patients who have an acute coronary syndrome, hyperten-

Drugs to treat hypotension

improvement with the use of salmeterol, however it is not clear whether

Gastric acid blockers

Sleep-related withdrawal syndromes of prescribed medications

characteristic of wakefulness, increases movement, and decreases SWS [90].

Interaction of medication with pre-existing sleep disorders

Box 1. Effect of drugs on pre-existing sleep disorders

Abbreviation: PLMS, periodic limb movements during sleep.

[82] Sammaritano M, Sherwin A. Eﬀect of anticonvulsants on sleep. Neurology 2000;54:

Eﬀects of Common Medications

Americans are sleep deprived and sleep disordered. Recent estimates

term; discussion of new trends in treatment strategies is indicated. This dis-

Regulated commonly used over-the-counter sleep aids

about OTC purchases to promote sleep. Most of these preparations include

Commonly used oﬀ-label prescription medication

Food and Drug Administration–approved hypnotic medications

Benzodiazepine receptor agonists

The g-aminobutyric acid receptor: structure and activation

intracellular chloride levels because of binding to the GABA receptor in-

Alpha subunit selectivity: clinical relevance

Principles for prescribing benzodiazepine receptor agonists

Adverse events with benzodiazepine receptor agonist use

research deﬁnitions of dependence making comparisons of the data diﬃcult,

Melatonin receptor agonists

Melatonin 1 and melatonin 2 receptors