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Chapter 19
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Sleep inCritical Illness
MichaelT.Y.Lam, AtulMalhotra, JamieNicoleLaBuzetta,
andBirenB.Kamdar
Keywords Critical illness · Sleep · Circadian rhythms · Delirium
Sleep fragmentation · Sleep disruption · Sleep deprivation · Intensive care unit
The importance of sleep to overall wellness and physiological homeostasis has
been increasingly appreciated. For critically ill patients in the intensive care unit
(ICU) setting, physiological disruptions are common, highlighting sleep as an
important factor in this vulnerable population. In this chapter, we review existing
literature on sleep in the ICU and provide ideas for future research. After providing
an overview of sleep in healthy and critically ill patients, we review tools to measure sleep and causes of sleep disruption in the ICU.We also highlight the impact
of sleep disruption on two systems that are essential to recovery: the immune system and brain.
M. T. Y. Lam · A. Malhotra
Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine
and Physiology, University of California San Diego Health, La Jolla, CA, USA
J. N. LaBuzetta
Department of Neurosciences, Division of Neurocritical Care, University of California San
Diego Health, La Jolla, CA, USA
B. B. Kamdar (
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine,
University of California San Diego Health, La Jolla, CA, USA
e-mail: kamdar@ucsd.edu
M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine,
Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_19
*)
431© Springer Nature Switzerland AG 2022
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M. T. Y. Lam et al.
Sleep Patterns intheICU
Sleep inHealthy Adults
An understanding of sleep in healthy adults (summarized in greater detail in other
chapters of this book) is necessary to appreciate the sleep experienced by critically ill patients. In healthy adults, sleep architecture—as measured using polysomnography (PSG)—is divided into non-rapid eye movement (NREM) sleep,
comprised of N1 (2–5% of total sleep time), N2 (45–55%), and N3 (3–15%), and
REM (20–25%). Sleep onset usually occurs within 10–20minutes, and the rst
REM period usually begins 90–120minutes into sleep. In healthy adults, total
consolidated nightly sleep time is usually 7–9hours. Arousals occur roughly ten
times per hour (even in normal individuals), although higher gures have been
reported [1–3].
The drive to sleep is primarily governed by two factors: homeostatic and circadian. The homeostatic drive refers to the impact of antecedent sleep deprivation on the urge to sleep, i.e., the longer an individual is awake, the more tired
they get and more pressure to sleep. The circadian drive is based on an endogenous body clock, which increases or decreases the propensity to sleep during the
24-hourday.
The importance of circadian rhythms has been well established in health and
in disease, as the circadian system—consisting of a central oscillator and peripheral “clocks”—can affect cells in nearly every vital organ system [4]. The clinical
relevance of the circadian system is represented by the disproportionate number
of myocardial infarctions and ischemic strokes that occur in the morning and
asthma ares that occur at night [5–7]. Sleep-wake coordination, rest-activity
maintenance, light-dark exposure, feeding timing, and social interactions follow
a circadian pattern and are modiable factors for circadian rhythm alignment [8, 9].
Sleep inCritically Ill Patients
In contrast to healthy adults, sleep in critically ill patients is characterized by low
total sleep time (~5hr) and interruption of the normal diurnal pattern, with approximately 50% of sleep occurring during daytime hours [10–14]. Critically ill patients
undergoing polysomnography (PSG) have been shown to experience mostly N1 and
N2 sleep, with notably reduced or absent slow-wave sleep (N3) and REM (Fig.19.1)
[10–14]. Sleep in the ICU is also severely fragmented, with frequent interruptions
and arousals resulting in discrete and frequent sleep episodes [10–14]. This sleep
fragmentation was highlighted in a landmark study demonstrating that critically ill
patients undergoing PSG experienced 41±28 sleep episodes each day, with each
episode averaging 15±9minutes [15].
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Fig. 19.1 Sleep patterns in critically ill patients, as recorded using polysomnography, as compared to a healthy adult. Gray areas represent sleep and white areas represent wakefulness; notable
in critically ill patients is the lack of consolidated sleep, N3 and REM.ICU intensive care unit,
REM rapid eye movement. (From Knauert, with permission [14])
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Sleep Measurement intheICU
Large-scale, accurate measurement of sleep in the ICU setting is challenging and
represents a key barrier to efforts aimed at building knowledge in this area.
Nevertheless, sleep measurement in the ICU is a topic of great interest motivating
many prior and ongoing investigations.
Polysomnography
In the ICU setting, PSG is cumbersome and expensive; furthermore, it is not feasible to perform for longer than 24hours [13]. Additionally, interpretation of the PSG
differs substantially when comparing prototypical critically ill patients with community-dwelling adults [16]. For example, while N2 sleep is characterized by sleep
spindles, benzodiazepines—sedative medications commonly used in the ICU—can
produce spindles on EEG that are qualitatively similar but functionally different
than those occurring during natural sleep. Thus, the N2 designation in the ICU can
be problematic due to its inability to discriminate between natural and benzodiazepine-induced N2. Similarly, N3 (slow-wave) sleep is characterized by delta activity,
a brain wave pattern also resembling that seen in ICU patients experiencing encephalopathy, i.e., diffuse slowing [14, 17, 18]. Finally, submentalis electromyography
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(EMG), which is commonly used for sleep staging (e.g., REM vs. NREM), can be
affected in the ICU setting by paralytics or comorbidities.
While ICU-based efforts to dene new criteria for sleep staging of PSG recordings are ongoing, no major consensus has been reached [16]. As a result, efforts to
evaluate the effectiveness of sleep interventions remain hampered by difculties in
assessing sleep, e.g., scoring sleep according to conventional methods.
M. T. Y. Lam et al.
Actigraphy
Actigraphy involves accelerometry, often via a wristwatch-like device, to evaluate
cycles of rest and activity. A decades-old technology, actigraphy has received recent
attention for large-scale use in the ICU since it is inexpensive and well tolerated and
can wirelessly capture continuous rest-activity data across daytime and nighttime
periods [19–21]. Moreover, as demonstrated in nursing home and ICU survivor
populations, actigraphic rest-activity data can be used to approximate circadian
rhythm alignment [22, 23]. Despite these strengths, actigraphy is challenging in the
ICU as critically ill patients are mostly inactive, resulting in overestimation of sleep
using traditional scoring algorithms [19, 20, 24]. Moreover, actigraphy-based activity monitoring can be confounded by common ICU factors such as sedating medications, delirium, and staff interventions such as turning and bathing. Nevertheless,
actigraphy is a promising method for capturing rest-activity rhythms in critically ill
patients, especially if ICU-specic scoring algorithms are developed.
Subjective Measures
Subjective measurement of sleep is a practical, low-cost option for evaluating sleep
at a large scale in the ICU.Currently, the Richards-Campbell Sleep Questionnaire
(RCSQ), which involves a 5-item visual analogue scale (VAS), and the Verran/
Snyder-Halpern Sleep Scale [25, 26]—which involves a 14-item VAS—represent
the most commonly used sleep questionnaires in the ICU [27–32]. The RCSQ is the
only instrument validated against PSG [26, 33]. While easy to collect and inexpensive to use in the ICU setting, subjective instruments have inherent limitations,
including recall bias and fatigue across repeated assessments. Notably, ICU staff
may complete subjective instruments for patients with altered cognition and/or consciousness [28, 34, 35]; however these ratings tend to be overestimated [36].
Whether by observation or validated instruments, subjective sleep measurement in
the ICU must be performed with caution.
Environmental factors
Patient factors
epine
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Causes ofSleep Disruption intheICU
The nature of the ICU environment could be described as a “constant routine” in
which noise, light, and biological stress occur 24/7. As such, critically ill patients
are felt to experience substantial circadian rhythm disruption, but data are sparse to
support the presence of circadian misalignment or the therapeutic benets of circadian rhythm entrainment in the ICU [4, 8, 9, 37, 38]. Several factors can contribute
to disrupted sleep in critically ill patients, many of which are modiable (Fig.19.2).
In theory, modulation of ambient light and noise, timing of food and medication
administration (e.g., melatonin, ramelteon), as well as adjusting mechanical ventilation could inuence sleep-wake rhythms highlighting these factors as potential targets for ICU-based interventions aimed at improving clinical outcomes [18, 39].
Noise
Noise, dened as an unpleasant, unwanted, and/or disruptive sound, is common in
the ICU setting [40, 41]. Noises produced by people (e.g., staff, visitors), machines
(e.g., ventilator alarms, IV pumps), or objects (e.g., doors, squeaky shoes) can
Ambient sound
Changes in sound level (e.g.
beeping monitor)
Unnatural timing and/or quality
of light
Temperature
Unfamiliarity
Sleep disorders and disordered
breathing
Medications and illicit substances
Pre-existing conditions and genetics
Increased age
Critical illness
Pain
Short-term
Agitation
Delirium
Sleep disruption in
the ICU
Neurocognitive
outcomes
Increased mortality and morbidity
Care-related factors
Frequent examinations
Ventilator dyssynchrony
Continuous sedation
(especially benzodiaz
administration)
Medication administration
Patient hygiene
Other interactions (e.g. lab
draws)
Long-term
Cognitive Dysfunction
PTSD, depression, anxiety
Disordered Sleep
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Fig. 19.2 Causes and consequences of sleep disruption in the ICU
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disrupt sleep [42, 43]. In the ICU, noise levels range from 55 to 65dB [15, 44–46]
but often exceed 80dB, a level sufcient for sleep arousal [47]. In comparison, the
Environmental Protection Agency recommends hospital noise levels average less
than 35–45dB during the day and 30–35dB at night [48]. Some data suggest that
absolute noise levels are less critical than sound-level changes [49]. Abrupt changes
in noise level—for example, an IV pump alarming in an otherwise quiet room—are
common in the ICU and may disrupt sleep more than constant background sounds.
Additionally, recent studies have shown that the majority of noise in the ICU originates from sources near the ears of the patient and is often due to staff conversations
and nonessential alarms [42, 43]. As patients and survivors consistently report noise
as a disruptive factor needing improvement [18, 50], efforts are needed to identify
and minimize noise in the ICU.
M. T. Y. Lam et al.
Light
Despite suboptimal day-night light exposure in the ICU setting, critically ill patients
generally report light to be less disruptive than other factors such as noise and carebased interactions [28, 51]. Nevertheless, mistimed, excessive, or inadequate environmental light exposure can affect sleep-wake rhythms. As described above and in
other chapters, sleep-wake rhythms follow a circadian pattern, with the suprachiasmatic nucleus (SCN) acting as a central 24-hour pacemaker. Light represents the
strongest zeitgeber (environmental cues that entrain the central clock) for sleepwake rhythms by regulating melatonin secretion from the SCN.Typically, retinal
receptors receive early morning light, which signal the SCN to suppress melatonin
secretion from the pineal gland. Melatonin levels accumulate in the early evening to
promote sleep.
When compared to indoor light (~1000 lux), subjects exposed to natural light
(>4000 lux) over longer durations have been shown to exhibit improved melatonin
and sleep-wake rhythms [52]. Unfortunately, in the ICU setting, light levels range
from 30 to 165 lux during the day, below the level needed to inhibit melatonin, and
can rise as high as 1445 lux at night, above the level needed to suppress melatonin
release [49, 53–57]. Light levels during bedside procedures have been shown to
reach 10,000 lux [56]. Interestingly, independent of light exposure, impaired melatonin secretion has been observed in patients with sepsis [58] and delirium [59, 60],
highlighting bright light exposure as a potentially important intervention in critically ill patients [56]. Additionally, melatonin and melatonin-receptor agonists are
receiving attention as part of ICU-based sleep-wake improvement efforts [61–66].
Care-Related Interactions
While vigilant monitoring is required in the ICU setting, in some circumstances
excessive or poorly timed staff interactions can be deleterious. For example, hourly
assessments may capture signs of deterioration early in an ICU course, but may
19 Sleep inCritical Illness
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disrupt sleep once a patient achieves clinical stability. When surveyed, ICU patients
report blood draws, vital signs, and nurse visits among the most disruptive factors,
along with radiographs, baths, wound care, and suctioning and non-care-related
interactions from family and visitors.
When quantied, ICU patients can experience up to 8 care-related interactions
per hour while sleeping [67] and 50 across the night shift [68, 69]. When evaluated
against PSG in one study, one out of every ve interactions resulted in a sleep
arousal or awakening [12]. Hence, efforts to improve sleep should involve individualization of bedside interactions, consideration of nondisruptive technologies (e.g.,
devices with outside-of-the-room alarms and controls), and bundling of care [70,
71]. Vital to such efforts is multidisciplinary and staff engagement to develop inter-
ventions to minimize interactions and to evaluate their feasibility [72].
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Medications
Via mechanisms including sympathetic activation, deliriogenicity, and drug-drug
interactions, nearly every medication administered in the ICU can disrupt patient
sleep (Table19.1). Notably, chronotherapy—treatments provided in the context of
the body clock—is gaining interest, as data suggest that the timing of treatment may
impact the safety and efcacy of various treatments [73]. For example, inhaled steroid use at 3pm has been shown to have similar efcacy to more frequent dosing
[74]. Additionally, chemotherapy may be safer and more effective when administered at specic times [75]. Understanding and optimizing the timing of medications in critically ill patients represents a compelling area of research, along with
other common ICU practices such as enteral feeding and mechanical ventilation.
Mechanical Ventilation
While mechanical ventilation (MV) is a cornerstone of critical care, inappropriate
patient-ventilator interactions can result in profound sleep disruption. In general,
patients receiving mechanical ventilation report worse sleep quality compared to
those not receiving MV, for various reasons including patient-ventilator dyssynchrony, endotracheal tube discomfort, alarms, and ventilator-related care interactions (i.e., suctioning) [51, 76, 77]. Additionally, small studies in patients receiving
MV suggest that spontaneous modes such as pressure support (PSV) may inhibit
sleep by inducing central apneas from intermittent bursts of excessive support [78].
Controlled modes of ventilation, such as volume control (VC), pressure control
(PC), and proportional assist ventilation (PAV), may be better for sleep, in particular
PAV via matching of driving pressure with patient effort [79]. However, one study
involving clinician-adjusted PSV [80] and another involving addition of dead space
to the ventilator circuit in patients receiving PSV [81] demonstrated improvement in
central apneas and associated sleep disruption as compared to PSV alone, suggesting that individualized instead of “one size ts all” approaches are vital for
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Table 19.1 Commonly used ICU medications and their effect on sleep
Medication class Mechanism of action Effect on sleep
Sedative
Benzodiazepines GABA receptor agonist ↓W, ↑TST, ↓N3, ↓REM,
↓SL
Dexmedetomidine α
-Agonist ↑N3, ↓SL, ↓REM, ↑N2
2
with spindles, ↑SE
Propofol GABA receptor agonist ↑TST, ↓SL, ↓W, ↓REM
Nonbenzodiazepine hypnotics GABA receptor agonist ↓N2, ↑TST, ↓N3, ↑↓REM,
↓SL, ↓W
Analgesic
Opioids μ-Receptor agonist ↓TST, ↓N3, ↓REM, ↑W
Antipsychotic
Haloperidol Dopamine-receptor antagonist ↑TST, ↑N3, ↑SE, ↓SL, ↓W
Olanzapine 5HT
Trazodone SSRI, 5HT
-, D2-receptor antagonist ↑TST, ↑N3, ↑SE, ↓SL, ↓W
2
antagonist, H
-receptor
1a/1c/2
-receptor antagonist
1
↑N3, ↑↓REM,? ↑SE, ↓SL
Antihistamine
Diphenhydramine H1-receptor antagonist ?↑N3, ↓REM,? ↑SE, ↓SL
Melatonin and melatoninreceptor agonist
Ramelteon Melatonin 1 and 2 receptor agonist ↑TST, ↓SL, ↑SE
Immunosuppressant
Corticosteroids Decreased melatonin secretion ↑W, ↓N3, ↓REM,
insomnia
Tacrolimus Calcineurin inhibitor Insomnia
Cyclosporine Inhibits production and release of
Insomnia
IL-2
Cardiovascular
Norepinephrine/epinephrine α- and β-receptor agonist ↓N3, ↓REM, insomnia
Dopamine D
Phenylephrine α
-, β1-, α1-receptor agonist ↓N3, ↓REM, insomnia
2
-Receptor agonist ↓N3, ↓REM
1
β-Blockers CNS β-receptor antagonist ↑W, ↓REM, nightmares,
insomnia
Amiodarone Various pathways Nightmares
Clonidine α
-Agonist ↓REM
2
Antimicrobial
Fluoroquinolones GABA type A receptor inhibition Insomnia
Abbreviations: ICU intensive care unit, GABA gamma-aminobutyric acid, W wake, TST total sleep
time, N2 deeper sleep, N3 restorative/slow-wave sleep, REM rapid eye movement sleep, SL sleep
latency, SE sleep efciency, SSRI selective serotonin reuptake inhibitor, CNS central nervous system, W wake
optimizing sleep quality. Other strategies to improve sleep quality could include
adjusting positive end-expiratory pressure (PEEP) to lessen respiratory effort for
patients with auto-PEEP, increasing the inspiratory ow rate in the setting of air
Neurological
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439
hunger, shortening inspiratory time to prevent double triggering, and minimizing
sleep-disrupting sedative medications. Additionally, modes such as neurally
adjusted ventilator assist (NAVA), which involves neuromechanical coupling to promote patient-ventilator synchrony, may also be considered [82]. While the 2018
Clinical Practice Guidelines for Pain, Agitation/Sedation, Delirium, Immobility,
and Sleep Disruption (PADIS) conditionally recommend controlled ventilation
modes for sleep at night, large multi-site studies are needed to ll substantial knowledge gaps [83].
Sleep, Immunity, andCognition inCritically Ill Patients
Sleep disruption can have a profound effect on nearly every major organ system,
thus impeding recovery for critically ill patients (Fig. 19.3). The SARS-CoV-2
(COVID-19) pandemic has increased attention toward critical care, specically
highlighting the poor sleep patients experience in the ICU setting [84] and its possible association with immune dysfunction [85] and—in the context of delirium and
dementia—cognitive dysfunction [86, 87]. As a summary of the multi-organ effects
of sleep disruption would be beyond the scope of this chapter, this section instead
will focus specically on the role of sleep disruption on immune and cognition
function in critically ill patients.
Pulmonary
• ↓ ventilatory response to
hypercapnia & hypoxemia
• ↑ upper airway
collapsibility leading to
more apneic events
• ↓ inspiratory muscle
endurance
Metabolic & endocrine
• Impaired fasting glucose
• Temperature
dysregulation
• ↓ growth hormone surge
• Shift in cortisol peak
• ↑ norepinephrine
Musculoskeletal
• Hyperalgesia
• ↑ risk of injury
• Depressed mood
• Circadian dysrhythmia
• ↓ cognitive processing (e.g.
memory)
• Delirium
Cardiovascular
• ↑ blood pressure
• ↑ blood pressure
variability
• Long-term: ↑
cardiovascular morbidity
Immune
Gastrointestinal
• Possible bacterial overgrowth
• Microinflammation → GI
symptoms
Inflammation Æ Sleep homeostasis
ICU-related inflammation
• Pathogens exposure
• Infection and sepsis
• Tissue injury
Altered inflammatory mediators
• IL1β
• TNFα
• Prostagladins
Altered sleep physiology
• ↑ Somnolence
• ↓ Sleep efficiency
• ∆ NREM
• ↓ REM
Sleep disruption Æ Immune function
ICU-related and chronic sleep disruption
• Acute sleep deprivation
• Chronic sleep insufficiency
Immune dysfunction
• ↑ Susceptibility to infection
• Altered adaptive immune
response (e.g. vaccination)
• Altered circulating cytokine levels
(IL6, IL1β)
• Altered peripheral immune cell
composition and functions
Antibody
production
Fig. 19.3 The effect of disrupted sleep on major organ systems, with a focus on the relationship
of poor sleep, immunity, and inammation. (Adapted from Chang etal. [146])
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M. T. Y. Lam et al.
Sleep andImmunity
Adequate sleep is critical to immune function (Fig.19.3). Outside of the ICU, clinicians and researchers observed the development of respiratory infections as a consequence of sleep deprivation, which has more recently been supported by
high-quality studies. First, a rhinovirus inoculation study in healthy human volunteers observed a higher rate of infection in subjects obtaining 7hours or less of
sleep, as compared to rested controls [88]. Second, in large epidemiological cohorts,
reported sleep duration of 5 hours—as compared to matched controls obtaining
7–8hours of sleep—has been associated with an increased incidence of pneumonia
[89] and upper respiratory tract infections [90]. Third, in response to inuenza [91,
92] and hepatitis vaccination [93, 94], a slowed peak in antibody levels has been
noted in those who are sleep deprived as compared to those obtaining adequate
sleep. The ndings may suggest an adequate but delayed antigenic response due to
sleep deprivation. Lastly, acute sleep deprivation in healthy individuals alters circulating cytokine levels [95] and the transcriptome relevant to immune function in
blood cells [96, 97]. While these studies suggest that sleep disruption may alter
humoral and cellular immunity, other studies suggest that chronic sleep disruption
may exacerbate inammatory states such as atherosclerosis [98–100], metabolic
syndrome [101–105], stroke [106, 107], and tumor immunity [108, 109] (Fig.19.3).
Reciprocally, infection also has an important relationship with sleep. Somnolence
is a cardinal symptom of infection, and sleep is therefore considered an acute-phase
compensatory response. In animal models, viral and bacterial infections, as well as
the inoculation of pathogenic components (e.g., muramyl peptide, lipopolysaccharide), are sufcient to alter sleep [110]. In a series of studies in healthy volunteers,
low doses of systemic endotoxin resulted in changes in sleep patterns on PSG, prolonging NREM sleep while suppressing REM sleep [111]. Moreover, sleep is
altered differentially depending on the timing and dosing of a septic challenge
[112], highlighting the complex relationship between acute inammation and sleep.
Indeed, the effect of sepsis on sleep architecture is likely inuenced by a complex
combination of factors, including cytokines IL (interleukin)-1β, TNF (tumor necrosis factor)-α, and prostaglandins [95].
In the ICU setting, the relationship between sleep disruption and immune function is unclear and complicated by the ubiquity of sleep disruption and infection in
critically ill patients. Research in animals has contributed valuable knowledge in
this area. Sleep-deprived mice have a higher mortality after a septic challenge as
compared to non-sleep-deprived controls [113–115], an observation that could be
attributed to impaired pathogen clearance [114]. Furthermore, as the somnogenic
effect of sepsis depends on a neuronal-specic isoform of IL1 receptor accessory
protein, mice decient of this gene lacked the sleep response when given a septic
challenge with inuenza and experienced higher mortality than controls [116].
Moreover, animals invariably died after 6–8weeks of chronic total sleep deprivation
[117] and showed signs of bacterial infection before death [118]. While these studies support the notion of compromised microbial defense as a consequence of sleep
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