REVIEW

C URRENT
OPINION Sleep in the intensive care unit
Eugenia Y. Lee a and M. Elizabeth Wilcox a,b

Purpose of review
Sleep is particularly important for critically ill patients. Here, we review the latest evidence on how sleep
and circadian disruption in the intensive care unit (ICU) affects physiology and clinical outcomes, as well
as the most recent advances in sleep and circadian rhythm promoting interventions including therapeutics.
Recent findings
On a molecular level, clock genes dysrhythmia and altered immunity are clearly linked, particularly in
sepsis. Melatonin may also be associated with insulin sensitivity in ICU patients. Clinically, changes in
sleep architecture are associated with delirium, and sleep-promoting interventions in the form of
multifaceted care bundles may reduce its incidence. Regarding medications, one recent randomized
controlled trial (RCT) on melatonin showed no difference in sleep quality or incidence of delirium.
Summary
Further investigation is needed to establish the clinical relevance of sleep and circadian disruption in the
ICU. For interventions, standardized protocols of sleep promotion bundles require validation by larger
multicenter trials. Administratively, such protocols should be individualized to both organizational and
independent patient needs. Incorporating pharmacotherapy such as melatonin and nocturnal
dexmedetomidine requires further evaluation in large RCTs.
Keywords
circadian rhythm, critical illness, intensive care, sleep

INTRODUCTION anterior hypothalamus. The SCN regulates multiple

Sleep is essential to good health and may play a key
role in the recovery of critically ill patients. This
state-of-the-art review will describe recent develop-
ments in the literature on sleep and circadian dis-
ruption specific to its regulation of immunity,
hormones, and neurocognitive function, particu-
larly delirium, during acute illness. Further, we will
describe the opportunities and challenges in imple-
neurotransmitter systems including the hypothal-
amo–pituitary–adrenal (HPA) axis and melatonin
secretion from the pineal gland [2]. These processes
cycle with time, with the period between one peak
(i.e., acrophase) and the next being roughly 24 h.
Normal circadian rhythmicity prepares the body for
periods of increased energy demand or stress,
enhancing the function of individual cells, organ
&

menting interventions to improve sleep and circa-
dian rhythmicity in the intensive care unit (ICU).
NORMAL SLEEP PHYSIOLOGY
Normal sleep is divided into nonrapid eye move-
ment (NREM) and rapid eye movement (REM)
stages, which cycle approximately every
90 min. NREM sleep is in turn divided into three
stages – N1 and N2 (light sleep) and N3 (deep or
restorative sleep). A review of the active processes
relevant to each of sleep stage is provided by Patel
et al. [1].
The sleep–wake cycle is regulated by two proc-
esses – a sleep homeostat (process S) driven by levels
of adenosine, and a circadian pacemaker (process C)
located in the suprachiasmatic nucleus (SCN) of the
systems or whole organisms [2,3,4 ].
ALTERED SLEEP AND CIRCADIAN
DISRUPTION IN THE ICU
In the ICU, patients typically sleep poorly. While
mean total sleep time is comparable between
a
Interdepartmental Division of Critical Care Medicine, University of
Toronto and bDepartment of Medicine, University Health Network,
Toronto, Canada
Correspondence to M. Elizabeth Wilcox, MD, PhD, Interdepartmental
Division of Critical Care Medicine, University of Toronto, University
Health Network, Toronto M5T 2S8, Canada.
Tel: +1 416 603 5800 ext. 6203; e-mail: elizabeth.wilcox@utoronto.ca
Curr Opin Pulm Med 2022, 28:515–521
DOI:10.1097/MCP.0000000000000912

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Sleep and respiratory neurobiology
KEY POINTS
 Disruptions in sleep and circadian rhythm may have
significant impact on both molecular physiology and
clinical outcomes, ranging from the immune system,
glucose homeostasis, delirium, and even mortality.
 Measuring sleep in the intensive care unit (ICU) is
challenging due to multiple confounding factors and
developing a reliable and practical sleep measurement
tool in the ICU is a priority for further study.
 Sleep promotion bundles with both
nonpharmacological and pharmacological interventions
may be the most promising way to address the
multidimensional nature of sleep and circadian
disruption in the ICU.
critically ill patients and healthy adults, sleep in the
ICU is more fragmented – periods of sleep are often
short, with approximately half of total sleep time
occurring during daytime hours [3,5]. Patients also
experience poor sleep efficiency, with a predomi-
nance of sleep stages N1 and N2 and a lack of
restorative N3 sleep and REM. Sleep architecture is
also disrupted. In a cohort study of 57 mechanically
ventilated patients, almost one-third of patients
demonstrated dissociative EEG findings, where slow
background EEG activity, typically associated with
deep sleep stages, was seen during behavioral wake-
fulness [6].
The loss of key environmental sensory cues (e.g.,
light required for photoentrainment) and/or patho-
logical disruption at a cellular level (e.g., sepsis) may
make critically ill patients particularly susceptible to
circadian rhythm disruption. The latter phenom-
enon is imperfectly understood but may relate to
the inflammatory response [7]. Animal models sug-
gest that the cellular effect on circadian rhythm
disruption seems to persist for weeks after a septic
insult [8]. Melatonin secretion in ICU patients can
be influenced by numerous factors including age,
benzodiazepines and other sedative use, administra-
tion of adrenergic compounds, ß-blockers, opiates,
light exposure, mechanical ventilation, and sepsis
[7,9]. The relative contribution of each of these
factors is unclear and may vary between patients.
In addition, the pattern of circadian rhythm dis-
turbance experienced by patients can vary. For
example, one patient with sepsis may experience
a loss of acrophase amplitude, whereas another may
experience a shift in the timing of their acrophase,
or even degradation to erratic fluctuations or com-
plete flattening [10].
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CONSEQUENCES OF ALTERED SLEEP AND
CIRCADIAN DISRUPTION IN THE ICU
Emerging evidence illustrates multiple physiologi-
cal and psychological consequences of sleep and
circadian rhythm disruption in critically ill patients,
some of which may impact upon important patient-
centered outcomes. We have focused on the impact
of sleep and circadian disruption in the ICU on
immunity, glucose homeostasis, and incidence
of delirium.
Immune system disturbances
The relationship between circadian rhythm and
immunology has been demonstrated in both animal
&
models and healthy humans [11 ]. In the cecal
ligation puncture model of sepsis, mice demon-
strated better bacterial clearance, reduced systemic
inflammation, and less kidney injury when exposed
to high-illuminance blue light, which mimics early
morning light [12]. In humans, shift-workers have
been shown to have an increased susceptibility to
infection which may, at least in part, be explained
by the phenomenon of light-at-night [13,14]. At a
molecular level, multiple immune cells display a
circadian rhythm with high expression of regulatory
clock genes, including CLOCK, BMAL, PER1-3 and
&
CRY1-2 [11 ]. Such associations mostly likely stem
from an evolutionary selection for mechanisms that
anticipate behavioral activity and feeding cycles,
impacting exposure risks to microbial pathogens.
In critically ill patients, there is evidence that
the circadian rhythmicity of both clock genes and
components of the immune system are disrupted in
parallel. Disruptions in the expression of key clock
genes have been seen in patients with severe sepsis
& &
[15 ,16 ,17], trauma [18], and critical neurological
illness [19 ]. Lachmann et al. [16 ] studied 20
& &
patients with septic shock by measuring 17 clock
and clock-associated genes isolated from their
monocytes. Overall rhythmicity scores of these
clock genes for septic shock patients were signifi-
cantly lower as compared to healthy adults. Further,
microarray data of 28 septic shock patients, eval-
uated at the onset of vasopressor initiation, devel-
oped major genomic alteration within the first 48 h
after shock affecting almost 75% of the human
genome [17]. Both pro- and anti-inflammatory proc-
esses, measured at the transcriptomic level, were
induced within the hours after septic shock. Inter-
estingly, the most severely ill septic patients did not
exhibit the strongest modulation [17]. In comparing
the expression of clock genes and plasma cytokines
in healthy individuals to both nonseptic and septic
patients in the ICU, Acuña-Fernández et al. [15 ] also
&
Volume 28  Number 6  November 2022

showed that clock gene rhythm was blunted in septic
patients, with an associated higher innate immune
and oxidative stress responses. Such derangements in
clock gene function have been linked to important
clinical outcomes. In a case series of 11 patients with
primary neurological injury, a temporal association
between clock gene disruption and length of ICU stay
was seen; initially at the time of admission circadian
rhythmicity of clock genes (CLOCK, Bmal-1, Cry1
and Per2) were preserved; however, at one week,
&
disrupted rhythmicity was seen [19 ]. Although these
associations are intriguing, a causal relationship is yet
to be established. As such, the potential of these clock
genes as therapeutic targets, for severe inflammatory
states in ICU patients, remains an area of intense
study.
Disruptions in glycemic control and insulin
sensitivity
The correlation between sleep deprivation and
changes in glycemic homeostasis is well established
in healthy adults. Prior studies on healthy volun-
teers have repeatedly demonstrated that short-term
sleep disruption (24 h to a few days) leads to lower
insulin sensitivity and impaired fasting and post-
prandial glucose levels [20]. Individuals with persis-
tent poor sleep and circadian rhythm disruption are
at increased risk of type 2 diabetes mellitus [20,21].
Further, there is increasing evidence that melatonin
may be associated with glucose metabolism. Dia-
betic patients have lower melatonin levels at night,
and long-term use of melatonin has been shown to
be associated with improved glycemic control in
both diabetes and polycystic ovarian syndrome [22].
In critically ill patients, hyperglycemia is a com-
mon issue associated with adverse clinical out-
comes. The association between sleep disturbance
and glycemic control is of special interest in the ICU.
Although existing literature has yet to demonstrate
a direct link between sleep and circadian rhythm
disruption and glucose dysregulation specifically in
critical illness, great interest exists in determining
the therapeutic effect of melatonin on glycemic
control. A recent study of 104 nondiabetic critically
ill patients tested this hypothesis with short-term
use of melatonin at a dose of 6 mg twice daily for
&
3 days, as compared to placebo [23 ]. Homeostasis
models of assessment for insulin resistance (HOMA-
IR) and adiponectin (HOMA-AD) ratios, based on
the ratio of fasting glucose and insulin levels were
&
assessed [23 ]. There was a significant decrease in
both glucose levels and HOMA-IR on the fourth day
&
of melatonin prescription [23 ]. Although this study
introduces the potential of melatonin in controlling
glucose in acutely ill patients, it did not study the
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Sleep in the intensive care unit Lee and Wilcox
direct relationship between insulin resistance and
sleep physiology or perception. Further study is
required to delineate the physiology, clinical rele-
vance, and potential application of melatonin and/
or sleep promotion in relation to glycemic control in
critically ill patients.
Delirium
Although sleep and circadian rhythm disruption are
regarded as potentially modifiable risk factors for
the development of delirium, a bidirectional rela-
tionship likely exists between delirium and sleep/
circadian rhythm disruption. Studies conducted
mainly in cardiac surgical patients indicate that
sleep deprivation can cause [24], be a result of
[25], or simply lower the threshold for transitioning
to delirium. A prospective cohort study of surgical
ICU patients demonstrated an association between
delirium and severe REM sleep reduction (<6% of
total sleep time) [26]. Similarly, in a single center
case–control study, critically ill patients who devel-
oped delirium during their stay experienced less
REM sleep compared to those who did not experi-
&&
ence delirium [27 ]. Further, delirious patients have
lower peripheral melatonin and cortisol levels, sug-
gesting an association between sleep disruption and
&&
delirium [27 ]. A recent American Thoracic Society
(ATS) research statement highlights that the mech-
anisms linking individual domains of sleep/circa-
dian disruption and delirium remain unclear in the
&
ICU population [28 ]. Furthermore, despite sleep
interventions seeming to be a promising approach
for improving delirium, studies to date have been
limited by small study sizes, confounders, and
variable methodology.
Hospital mortality
In addition to its association with various end organ
dysfunctions, poor sleep in the ICU has been shown
to have prognostic value. In an observational cohort
study of 93 medical patients, changes in sleep archi-
tecture – specifically the lack or absence of defining
EEG features in N2 sleep, including K complexes and
sleep spindles – was associated with severity of
encephalopathy and increased risk of death [29].
In a large administrative dataset review of 3837
patients with sepsis, preservation of a day-night
cycle, determined by heart rate and blood pressure
variability, was associated with increased survival
after accounting for age, vasopressor use, sedation,
and ventilator dependence [30]. These studies are
preliminary and are require confirmation in differ-
ent ICU patient populations. If sleep and circadian
rhythm disruption prove to be associated with
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Sleep and respiratory neurobiology

mortality, it may present an opportunity for in ICU
population enrichment for trials or serve as an inter-
mediate end point for long-term follow-up studies.
MEASURES OF SLEEP IN THE ICU
One of the limitations of studying sleep, and its
attributable risk to various outcomes, in the ICU
is that many patient-related, disease-related, and
environmental factors can confound the interpre-
tation of traditional sleep measurement tools. As
such, studying sleep and the impact of sleep inter-
ventions in the ICU presents a unique challenge.
Multiple objective and subjective measurement
tools for sleep exist; those commonly used in the
& &&
ICU are summarized in Table 1 [4 ,31,32 ]. Unfortu-
nately, there is currently no single validated tool
that can be reliably, practically, and broadly applied
in critical illness for consistent sleep and circadian
assessment. This was identified as a clear knowledge
gap and area of intense research in a recent ATS
&
research statement [28 ]. Studies for both estab-
lished and novel methods are ongoing in hopes to
achieve optimal measurement in each dimension of
sleep pathology.
INTERVENTIONS TO IMPROVE SLEEP AND
CIRCADIAN RHYTHM IN THE ICU
In a recent systematic review, multiple risk factors
for poor sleep in the ICU were identified, meaning
the relative contribution of each individual compo-
&&
nent is likely variable [33 ]. Although a general
approach to modifiable factors is convenient, this
proves challenging given the high variability of
patient-reported impact for different interventions.
As a result, the approach to improve sleep in the ICU
may need to be multidimensional yet individual-
ized. An evidence-based proposed protocol for sleep-
promoting bundles in the ICU is illustrated in Fig. 1.

Table 1. Advantages and limitations of available objective and subjective tools to measure sleep in an ICU patient population
Description Advantages Limitations

Polysomnography Based on EEG, EOG, EMG, ECG
(PSG) and other clinical parameters
such as oxygen saturation,
respiratory movement and
oronasal airflow
Partial PSG and 1. Single-channel EEG
processed 2. Multichannel EEGs
EEGs 4. Processed EEGs, e.g.,
Bispectral Index
Actigraphy Motion sensor detector used to
assess motor activity against a
specific sleep algorithm; usually
worn on wrist or ankles
Clinician Sleep observation tool (SOT):
observation nurse-administered assessment
tools at 15-min intervals, scoring the
patient as (1) asleep, (2)
awake, (3) could not tell, or (4)
no time to observe after a 5 s
observation.
Patient Richard Campbell Sleep
perception Questionnaire (RCSQ): a five-
tools item visual analog scale
measuring five domains of
sleep -- (1) sleep latency, (2)
sleep efficiency, (3) sleep
depth, (4) number of
awakenings, (5) overall sleep
quality
Gold standard for assessment
of sleep physiology and
sleep stages
 Provides real-time
physiological data
 Less intrusive and thus
better tolerated by patients
 Less labour-intensive
 Less intrusive and thus
better tolerated by patients
 Easier to use
 Requires less provider
training to apply
 Easy to integrate into
routine clinical practice and
daily ICU workflow (similar
to integration of CAM-ICU
for delirium assessment)
 SOT is the only clinician-
led subjective assessment
tool validated against PSG
 RCSQ is the only patient-
based subjective sleep
assessment tool validated
against PSG
 Validated in multiple
languages
 Recommended in PADIS
2018 guidelines
 Easy to use
 Low cost
 Difficult to apply standard scoring
criteria in critically ill patients
 Poorly tolerated by patients
 Labour-intensive
 Requires expertise in interpretation
 Not validated against full PSG
 More crude assessment compared to
PSG, thus interpretation against standard
scoring criteria even more difficult
 Artefacts common from care activities
 Does not account for sedation and
immobility
 Current evidence for validation against
PSG limited; evidence heterogenous with
small sample sizes
 Inter-user reliability not yet established
 Lack of correlation to other dimensions of
sleep such as sleep latency, sleep
architecture, and number of awakenings
 Recall bias
 Limited by delirium or sedation, which is
common in ICU (up to 50% of all ICU
patients)

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 Sleep in the intensive care unit Lee and Wilcox

FIGURE 1. Proposed components of a sleep promotion bundle in the ICU. A timeline-based diagram featuring major
components of sleep promotion bundles. Included are four domains of intervention including light (yellow), noise (red), care
activities (green), and pharmacotherapy (blue). There are three stages of implementation, as listed in the figure as A, B, and C
respectively. Stage A represents nonpharmacotherapy for all patients, stage B as nonpharmacotherapy only for nondelirious
patients, and stage C as additional therapies that have lower levels of evidence, but can be considered and individualized to
patient needs.

Nonpharmacological interventions levels in the ICU, and delirium frequency was

Given the multifactorial nature of sleep disruption
in the ICU, there is increasing interest in develop-
ing multicomponent sleep improvement bundles
& &&
[31,34 ,35]. By implementing a multifaceted sleep-
promoting bundle for 300 general medical-surgical
ICU patients, Kamdar et al. [36] showed a reduction
in delirium incidence in the postimplementation
phase as compared to baseline. This was in the
absence however of improvements in perceived
sleep quality [36]. This bundle was comprehensive
and included diurnal variations in three key mod-
ifiable environmental domains: lighting, noise,
and care activities. More recently, Topcu et al.
&&
[37 ] applied a similar protocol in 78 patients
(38 intervention group; 40 in the control group)
for a median duration of 7 days. There was signifi-
cant improvement in sleep quality; RCSQ scores
showed a strong negative correlation with noise
reduced from 60% at baseline to 45% in the inter-
&&
vention phase [37 ]. This difference, however, was
not statistically significant. Contrary to this, a
study by Darby et al. [38 ] incorporating a similar
sleep bundle into the existing ABCDEF bundle for
delirium prevention did not show any improve-
ment in sleep quality or rates of delirium. Definitive
conclusions are challenged however by missing
data within studies, particularly as it relates to
compliance with assessments of delirium and sleep
quality. Large, multicenter studies operationalizing
standardized tools for sleep assessment, detailed
descriptions of both unit- and organization-specific
processes of care, and acknowledgement of prior-
ities as well as existing practice culture may help to
better delineate the differential impact of sleep
bundles components on patient-centered out-
comes such as delirium.

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Sleep and respiratory neurobiology
Pharmacological interventions
Dexmedetomidine, an a-2-adrenergic agonist, dif-
fers in pharmacologic mechanism from traditional
sedatives used in the ICU. Its properties as a respi-
ration-sparing medication with analgesic, anes-
thetic, and sympatholytic properties, has made it
increasingly popular as a sedative in mechanically
ventilated patients [39]. Recently, nocturnal use of
dexmedetomidine has shown promise in sleep man-
agement in the ICU by improving sleep efficiency,
decreasing percentage of daytime sleep, and increas-
ing stage 2 sleep [40]. In a randomized controlled
trial of 100 mechanically ventilated delirium-free
patients, nocturnal dexmedetomidine infusion was
associated with lower incident delirium, however
subjective assessment of sleep was unchanged [41].
Importantly, sedatives such as GABA agonists were
halved at night as part of the study protocol [41].
The impact of sedative reduction on the primary
outcome of delirium is unknown. Therefore, while
nocturnal dexmedetomidine may play a role in
sleep improvement and delirium prevention, evi-
dence of its benefit is preliminary and further
studies are required before widespread use can
be recommended.
Alternatively, melatonin, known for its promi-
nent role in the sleep–wake cycle, has consistently
drawn considerable interest in its role to promote
sleep in critically ill patients. Prior studies have been
limited by small sample sizes, heterogeneity in
methods of sleep assessment and multiple potential
confounders [42]. Recently, Wibrow et al. [43 ]
&&
conducted a multicenter, double-blind RCT of 847
patients comparing 4 mg melatonin to placebo at
21:00 h for 14 consecutive nights or until ICU dis-
charge, initiated within 48 h of ICU admission.
There was no significant difference in the propor-
tion of delirium-free assessments between groups,
nor any difference in sleep quantity or quality.
This is the largest RCT investigating pharmacolog-
ical delirium prevention in combination with the
measurement of sleep. Several trials (clinicaltrials.
gov [assessed June 15, 2022]: NCT03524937,
NCT02615340, NCT03013790) are currently under-
way, assessing the role of melatonin for delirium in
addition to sleep bundle management; melatonin
being administered within the context of other
bundled nonpharmacological approaches of sleep
promotion. Currently, the 2018 PADIS guidelines
make no recommendations regarding the pharma-
cological management of sleep in the ICU [31].
Furthermore, it is likely that any pharmacologic
therapy will likely be most beneficial as one of the
components in a multidimensional and multidisci-
plinary sleep promotion bundle.
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CONCLUSION
Sleep is a multidimensional process that has signifi-
cant physiological and psychological consequences.
This is particularly evident in critically ill patients –
extreme physiological changes and aggressive
therapeutics in critical illness, multiple underlying
premorbid conditions, and uniquely disruptive
environmental factors all layer onto the complexity
of altered sleep and circadian rhythm in the ICU.
While the body of literature on the mechanisms and
pathophysiology to these disruptions is growing,
most evidence is heterogeneous and its true impact
on clinical outcomes remains unclear. Sleep promo-
tion bundles consisting of nonpharmacological and
pharmacological interventions may be the answer
to such a multidimensional process. However, larger
studies with consistent signal to benefit are needed
to shift practice culture to include sleep and circa-
dian rhythm care in evidence-based care bundles.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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www.co-pulmonarymedicine.com 521