Propofol For The Promotion of Sleep in Adults in The Intensive Care Unit (Review)

Cochrane Database of Systematic Reviews
Propofol for the promotion of sleep in adults in the intensive

care unit (Review)
Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF
Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF.

Propofol for the promotion of sleep in adults in the intensive care unit.
Cochrane Database of Systematic Reviews 2018, Issue 1. Art. No.: CD012454.
DOI: 10.1002/14651858.CD012454.pub2.
www.cochranelibrary.com
Propofol for the promotion of sleep in adults in the intensive care unit (Review)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 50
Propofol for the promotion of sleep in adults in the intensive care unit (Review) i
[Intervention Review]
Propofol for the promotion of sleep in adults in the intensive

care unit
Sharon R Lewis1 , Oliver J Schofield-Robinson2 , Phil Alderson3 , Andrew F Smith4

1
Patient Safety Research Department, Royal Lancaster Infirmary, Lancaster, UK. 2 Research and Development, Royal Lancaster Infir-
mary, University Hospitals of Morecambe Bay, NHS, Lancaster, UK. 3 National Institute for Health and Care Excellence, Manchester,
UK. 4 Department of Anaesthesia, Royal Lancaster Infirmary, Lancaster, UK
Contact address: Sharon R Lewis, Patient Safety Research Department, Royal Lancaster Infirmary, Pointer Court 1, Ashton Road,
Lancaster, LA1 4RP, UK. Sharon.Lewis@mbht.nhs.uk, sharonrlewis@googlemail.com.
Editorial group: Cochrane Anaesthesia, Critical and Emergency Care Group.

Publication status and date: New, published in Issue 1, 2018.
Citation: Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF. Propofol for the promotion of sleep in adults in the intensive care
unit. Cochrane Database of Systematic Reviews 2018, Issue 1. Art. No.: CD012454. DOI: 10.1002/14651858.CD012454.pub2.
ABSTRACT
Background
People in the intensive care unit (ICU) experience sleep deprivation caused by environmental disruption, such as high noise levels
and 24-hour lighting, as well as increased patient care activities and invasive monitoring as part of their care. Sleep deprivation affects
physical and psychological health, and people perceive the quality of their sleep to be poor whilst in the ICU. Propofol is an anaesthetic
agent which can be used in the ICU to maintain patient sedation and some studies suggest it may be a suitable agent to replicate normal
sleep.
Objectives
To assess whether the quantity and quality of sleep may be improved by administration of propofol to adults in the ICU and to assess
whether propofol given for sleep promotion improves both physical and psychological patient outcomes.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 10), MEDLINE (1946 to October 2017),
Embase (1974 to October 2017), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1937 to October 2017)
and PsycINFO (1806 to October 2017). We searched clinical trials registers for ongoing studies, and conducted backward and forward
citation searching of relevant articles.
Selection criteria
We included randomized and quasi-randomized controlled trials with adults, over the age of 16 years, admitted to the ICU with
any diagnoses, given propofol versus a comparator to promote overnight sleep. We included participants who were and were not
mechanically ventilated. We included studies that compared the use of propofol, given at an appropriate clinical dose with the intention
of promoting night-time sleep, against: no agent; propofol at a different rate or dose; or another agent, administered specifically to
promote sleep. We included only studies in which propofol was given during ’normal’ sleeping hours (i.e. between 10 pm and 7 am)
to promote a sleep-like state with a diurnal rhythm.
Data collection and analysis
Two review authors independently assessed studies for inclusion, extracted data, assessed risk of bias and synthesized findings.
Propofol for the promotion of sleep in adults in the intensive care unit (Review) 1
Main results
We included four studies with 149 randomized participants. We identified two studies awaiting classification for which we were unable
to assess eligibility and one ongoing study.
Participants differed in severity of illness as assessed by APACHE II scores in three studies and further differences existed between com-
parisons and methods. One study compared propofol versus no agent, one study compared different doses of propofol and two studies
compared propofol versus a benzodiazepine (flunitrazepam, one study; midazolam, one study). All studies reported randomization and
allocation concealment inadequately. We judged all studies to have high risk of performance bias from personnel who were unblinded.
We noted that some study authors had blinded study outcome assessors and participants for relevant outcomes.
It was not appropriate to combine data owing to high levels of methodological heterogeneity.
One study comparing propofol with no agent (13 participants) measured quantity and quality of sleep using polysomnography; study
authors reported no evidence of a difference in duration of sleep or sleep efficiency, and reported disruption to usual REM (rapid eye
movement sleep) with propofol.
One study comparing different doses of propofol (30 participants) measured quantity and quality of sleep by personnel using the
Ramsay Sedation Scale; study authors reported that more participants who were given a higher dose of propofol had a successful diurnal
rhythm, and achieved a greater sedation rhythmicity.
Two studies comparing propofol with a different agent (106 participants) measured quantity and quality of sleep using the Pittsburgh
Sleep Diary and the Hospital Anxiety and Depression Scale; one study reported fewer awakenings of reduced duration with propofol,
and similar total sleep time between groups, and one study reported no evidence of a difference in sleep quality. One study comparing
propofol with another agent (66 participants) measured quantity and quality of sleep with the Bispectral Index and reported longer
time in deep sleep, with fewer arousals. One study comparing propofol with another agent (40 participants) reported higher levels of
anxiety and depression in both groups, and no evidence of a difference when participants were given propofol.
No studies reported adverse events.
We used the GRADE approach to downgrade the certainty of the evidence for each outcome to very low. We identified sparse data
with few participants, and methodological differences in study designs and comparative agents introduced inconsistency, and we noted
that measurement tools were imprecise or not valid for purpose.
Authors’ conclusions
We found insufficient evidence to determine whether administration of propofol would improve the quality and quantity of sleep
in adults in the ICU. We noted differences in study designs, methodology, comparative agents and illness severity amongst study
participants. We did not pool data and we used the GRADE approach to downgrade the certainty of our evidence to very low.
PLAIN LANGUAGE SUMMARY

Propofol at night to improve sleep in the intensive care unit
Background
Lack of sleep affects a person’s physical and mental health and, for people who are critically ill, sleep is thought to improve healing and
survival. People in the intensive care unit (ICU) experience poor sleep. Many factors contribute to poor sleep including high noise levels,
24-hour lighting and intrusive patient care activities. Propofol is an anaesthetic agent given by infusion into a vein that is sometimes
used to sedate people who are in the ICU. In this review, we looked at studies in which propofol was given to adults at night-time to
improve the quality and quantity of sleep.
Study characteristics
The evidence is current to October 2017. We included four randomized controlled studies (clinical studies where people are randomly
put into one of two or more treatment groups) with 149 participants in the review. Two studies are awaiting classification (because we
could not assess their eligibility) and one study is ongoing. All participants were critically ill and were in the ICU.
Key results
We did not combine the results from the studies because of differences in comparison (called control) treatments and study design. One
study compared propofol with no agent. This study used polysomnography (which records brain waves, oxygen level in blood, heart
rate, breathing, and eye and leg movements) to measure sleep quality and quantity. It reported no improvement in duration of sleep
with propofol but participants woke up less often and for shorter lengths of time and described their sleep quality as being improved
with propofol. One study compared a higher dose of propofol at night described as additional night sedation, with a constant day-
time and night-time dose. This study used the Ramsay Sedation Scale (which is normally used by anaesthetists to assess how easily
a person is roused) and reported that participants appeared to have an improved sleep rhythm. Two studies compared propofol with
benzodiazepines (a tranquilizing medicine; flunitrazepam in one study and midazolam in one study). These studies used the Pittsburgh
Sleep Diary and the Hospital Anxiety and Depression Scale to measure quantity and quality of sleep. The study with flunitrazepam
reported fewer awakenings of reduced duration with propofol but similar total sleep time in each group and the study with midazolam
reported no difference in sleep quality. The study with flunitrazepam also measured sleep with Bispectral Index (used by anaesthetists
to assess depth of anaesthesia) and reported longer time in deep sleep, with fewer awakenings. The study with midazolam reported
higher levels of anxiety and depression in both groups, and no difference when participants were given propofol. No study reported on
side effects.
Quality of evidence
We judged the evidence to be very low quality. We found only four small randomized controlled studies and the results of the studies
were not consistent. We noted differences in illness severity of participants and the medicines that were compared with propofol in the
included studies. Measuring quality of sleep using diaries, questionnaires and scoring systems is based on, or is influenced by, personal
feelings or opinions, and we were concerned that staff and participants were aware which medicine they had been given; we believed that
this could have influenced the results. Only one study used polysomnography, which is the most appropriate unbiased measurement
tool for sleep.
Conclusions
We were unable to collect sufficient evidence to determine whether propofol given at night to adults in the ICU improves quality and
quantity of their sleep, as a way of helping recovery.
Propofol for the promotion of sleep in adults in the intensive care unit (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Propofol for the promotion of sleep in the intensive care unit versus no agent
Patient or population: critically ill adults in the intensive care unit

Settings: intensive care unit, Greece
Intervention: propof ol given to prom ote overnight sleep
Comparison: no agent
Outcomes Impacts No of Participants Quality of the evidence Comments

(studies) (GRADE)
Quantity and quality of sleep as Not reported. - - -

measured through reports of par-
ticipants or family members or
by personnel assessments
Data collected at end of study
f ollow-up
Quantity and quality of sleep as Outcom e m easured by PSG. 13 (1 study) ⊕ We identif ied only 1 study and could
measured by PSG, actigraphy, Study authors reported no evi- Very low1 not conduct a m eta-analysis
BIS or EEG dence of a dif f erence in duration
Data collected at end of study of sleep or sleep ef f iciency, and
f ollow-up reported disruption to usual REM
sleep with propof ol
Anxiety or depression, or both, as Not reported. - - -

measured using validated tools
f ollow-up
Adverse events (such as car- Not reported. - - -

diovascular events, respiratory
events or illness resulting from
immune deficiency)
BIS: Bispectral Index; EEG: electroencephalogram ; PSG: polysom nography; REM : rapid eye m ovem ent.
4
GRADE Working Group grades of evidence

High quality: f urther research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate quality: f urther research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low quality: f urther research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low quality: we are very uncertain about the estim ate.
1 Highlevel of perf orm ance bias; downgraded by one level. Data f rom single study with f ew participants; downgraded two
levels f or im precision.
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5
BACKGROUND movement, can be used to assess sleep. People in the ICU have
alterations to their circadian rhythm, with up to 50% of sleep oc-
curring during the day and with sleep arousals occurring as often
Description of the condition as 39 times per hour in people who are mechanically ventilated
(Parthasarathy 2004). Changes to sleep ’architecture’ are signifi-
It is accepted that sleep is an essential requirement for good health.
cant, with reductions in both REM and N3 sleep (Cooper 2000;
Sleep has a restorative function and for critically ill people is
Drouot 2008).
thought to improve healing and survival (Tembo 2009).
Empirical evidence on immediate and long-term physical con-
Sleep naturally follows a circadian rhythm of approximately 24
sequences of sleep deprivation for people in the ICU is limited,
hours, in a pattern of once a day. Each period of sleep consists of
but data suggest that sleep loss in healthy study participants can
phases lasting 90 minutes, with typical sleep ’architecture’ involv-
result in physical alterations to the immune system, as well as
ing a period of rapid eye movement (REM) and non-rapid eye
changes in metabolism, nitrogen balance, and the ventilatory and
movement (NREM). The NREM stage is subdivided into three
cardiovascular systems (Kamdar 2012a; Matthews 2011; Pisani
phases, now labelled as N1, N2 and N3 (also described as ’slow
2015; Weinhouse 2006). For example, after loss of only one night’s
wave patterns’). The REM stage accounts for 15% to 20% of sleep
sleep, biomarkers are released that are present in people with coro-
time, and N2 of NREM for approximately 50% (Matthews 2011;
nary artery disease (Sauvet 2010), although no longitudinal stud-
Schupp 2003; Silber 2007).
ies have demonstrated that sleep disturbance in the ICU results in
It is likely that people in hospital will be subject to sleep distur-
increased cardiovascular mortality (Kamdar 2012a). Psychological
bances; this is particularly likely for people in the intensive care
consequences associated with sleep loss, such as cognitive dysfunc-
unit (ICU). These people are critically ill with diagnoses such as
tion, depression and poor quality of life measures, affect hospital
respiratory insufficiency or failure, need for postoperative man-
length of stay, morbidity and mortality in critically ill people (e.g.
agement, ischaemic heart disorder, sepsis and heart failure (Society
Ely 2004). Psychological symptoms, such as post-traumatic stress,
of Critical Care Medicine). People may require specialist support
may persist for several months after ICU discharge (Eddleston
after elective surgery or may be emergency admissions following
2000; Figueroa-Ramos 2009; Kamdar 2012a; Matthews 2011).
medical events or trauma (e.g. with multiple injuries after a road
traffic accident) (Intensive Care Foundation).
In the ICU, the ratio of staff to patients is higher than in general
wards, and the environment typically includes 24-hour lighting, Description of the intervention
a constant level of noise and more frequent patient care activities Non-pharmacological interventions, such as noise and light reduc-
(measuring blood pressure, pulse and temperature; taking blood tion strategies (e.g. earplugs, eye masks; Richardson 2007), have
samples; administering medications, etc.) than in general wards. been studied specifically in the ICU, and some have been shown to
Many people (up to 40%; Esteban 2000) are mechanically venti- improve the quality of sleep. One Cochrane systematic review has
lated and are subject to invasive procedures such as tracheal intu- explored the effectiveness of these various strategies (Hu 2015).
bation and use of nasogastric tubes (Esteban 2000). In addition, The present review aimed to look at the anaesthetic agent propofol
people in the ICU have critical conditions that involve pain, anx- as administered to adults in the ICU to promote sleep. This agent
iety and stress (Kamdar 2012a). has the benefit of a rapid onset and offset, with a duration of action
Patients are often prescribed drugs that further contribute to sleep of 10 to 15 minutes (Brown 2001). It is given as a continuous
loss. For example, drugs such as benzodiazepines are given for es- intravenous infusion to induce and then maintain a state of general
sential sedation (particularly to people who are mechanically ven- anaesthesia. Given at different doses, it can initiate different levels
tilated) to relieve discomfort and stress. These agents alter sleep of consciousness on a continuum. It is currently among agents
architecture, such that N2 of NREM is longer than normal, which used in the ICU to maintain sedation (Grounds 2014).
may increase sleep time. However, they also reduce essential REM
and N3 phases of sleep (Bourne 2004). Similarly, opioids are com-
monly used for analgesia in the ICU, and studies report that these,
even when given in low doses and to healthy volunteers, reduce
How the intervention might work
the amount of deep sleep by up to 50% (Dimsdale 2007; Grounds Murphy 2011 used a high-density electroencephalogram (EEG)
2014). on healthy participants anaesthetized with propofol and noted
People perceive that the quality of their sleep in the ICU is similarities to readings from PSG assessments of normal sleep. In
disrupted by frequent awakenings and increased daytime sleep particular, the slow waves produced after administration of propo-
(Freedman 1999). This perception is supported by trials that as- fol were similar (although not identical) in appearance to those
sessed sleep by using objective measures. Polysomnography (PSG) seen during NREM of normal sleep. Results of animal studies sug-
readings, which use a variety of channels to measure electrical gested that recovery from sleep deprivation after propofol use is
activity of the heart, as well as muscle tension, airflow and eye similar to naturally occurring sleep patterns (Tung 2004).
These study results suggest that propofol may be a suitable agent Types of participants
for replicating normal sleep. Given its rapid onset and offset, We included adults, over 16 years of age, who were admitted to any
propofol can be administered at time points to maintain a person’s ICU as an elective or emergency patient, with medical, trauma or
usual diurnal rhythm and is a familiar drug in the ICU setting. surgical primary diagnosis. We did not limit types of participants
by severity of the condition. We included participants who were
and were not mechanically ventilated.
Why it is important to do this review

In 2014, the James Lind Alliance, a priority setting organization Types of interventions
that works with patients, carers and clinicians to establish research We included studies that compared the use of propofol, given at an
priorities for health care, published its top 10 priorities for research appropriate clinical dose with the intention of promoting night-
in the intensive care setting (www.jla.nihr.ac.uk/priority-setting- time sleep, against:
partnerships/intensive-care/top-10-priorities/). Among these are 1. no agent;
research topics relevant to enhancing patient comfort in the ICU 2. propofol at a different rate or dose; or
(including minimizing pain, discomfort, agitation and anxiety), 3. another agent, administered specifically to promote sleep.
preventing physical consequences of critical illness and providing We anticipated difficulties with terms used by study authors in this
psychological support for patients. review, in particular, the terms ’sleep’ and ’sedation.’ Participants
Although sleep disruption may affect many people in hospi- may be given propofol during the day with the aim of reducing
tal, those in the ICU are particularly vulnerable to disturbances consciousness as part of routine treatment in the ICU; this reduc-
that may subsequently lead to physical and psychological con- tion in consciousness may be referred to as ’sedation.’ We included
sequences, such as those identified above. Uncertainties remain only studies in which propofol was given during ’normal’ sleeping
about the benefits of pharmacological agents given to promote hours (i.e. between 10 pm and 7 am) to promote a sleep-like state
patient sleep in the ICU. It is unknown whether effectively pro- with a diurnal rhythm.
moting sleep will improve patient outcomes and provide imme- Participants given propofol for daytime sedation may also be given
diate and long-term clinical benefits. This review addressed the propofol as an intervention agent to promote sleep. We included
James Lind Alliance priority targets by assessing the effectiveness only studies in which study authors specified that propofol was
of propofol for sleep promotion in the ICU setting. given at night-time at a higher dose and with a different stated aim,
for example, to promote a diurnal rhythm. We did not specify the
dose or rate of administration; a ’lower’ daytime dose of propofol
given to achieve sedation may differ between participant groups,
depending on the severity of the condition of participants and
OBJECTIVES whether participants were mechanically ventilated.
We anticipated that study authors may have used scales to deter-
To assess whether the quantity and quality of sleep may be im- mine levels of participant consciousness, and we planned to report
proved by administration of propofol to adults in the ICU and to study authors’ interpretations of these scales. For example, par-
assess whether propofol given for sleep promotion improves both ticipants may be sedated at level 3 on the Ramsay Sedation Scale
physical and psychological patient outcomes. (“Patient responds to commands only”) and may be in a sleep-like
state at level 4 or 5 on this scale (“Patient exhibits brisk response to
light glabellar tap or loud auditory stimulus” or “Patient exhibits a
sluggish response to light glabellar tap or loud auditory stimulus”)
METHODS (Ramsay Sedation Scale).
It is reasonable that study participants may routinely be given other
agents that have a sedative effect, for example, benzodiazepines
or dexmedetomidine. We planned to record this information at
Criteria for considering studies for this review the data collection stage and assess whether it was balanced be-
tween study arms. We planned to include these agents in the com-
parison ’propofol versus another agent, administered specifically
to promote sleep’ only if they had been given to all participants
Types of studies
randomized to receive the comparative agent as part of the study
We included randomized controlled trials (RCTs) and quasi-ran- protocol, rather than routinely to all participants. We planned to
domized controlled trials (e.g. studies in which participants were include multi-arm studies, for example, those that compared dif-
assigned by alternation, date of birth or medical record number). ferent doses of propofol versus a different agent, only if each agent
was used as a comparative agent by randomized participants as adverse events as defined by study authors and diagnosed by clin-
part of the study protocol. icians at study level, such as cardiovascular or respiratory events
and illness resulting from immune deficiency. We assessed psycho-
Types of outcome measures logical consequences of sleep loss by collecting data from studies
that reported the number of participants who had been given a
We were interested in quantity and quality of sleep. The experi-
diagnosis of anxiety or depression, or both, by using validated as-
ence of sleep may not always be representative of objectively mea-
sessment tools during follow-up, as defined by study authors.
sured sleep, and given that people perceive that they have dis-
rupted sleep while in the ICU (Freedman 1999), we included this
outcome, regardless of whether validated scales had been used for Primary outcomes
measurement. An added issue for this outcome is that critically ill 1. Quantity and quality of sleep as measured through reports
people may have limited or no ability to communicate. Therefore, of participants or family members or by personnel assessments.
we were equally interested in the perceptions of carers and family 2. Quantity and quality of sleep as measured by PSG,
members, who may have had an impression of sleep from the bed- actigraphy, BIS or EEG.
side, and in subjective measures used by personnel to assess sleep.
We included assessments of sleep that had been performed at the
Secondary outcomes
end of follow-up, as defined by study authors, for example, in the
morning or during the daytime that followed administration of the 1. Anxiety or depression, or both, as measured using validated
intervention. We included assessments that were completed using tools, such as the Hospital Anxiety and Depression Scale
scales, whether validated or not and modified for each user, such as (HADS) (Zigmond 1983).
the Richards-Campbell Sleep Questionnaire (Richards 2000), or 2. Adverse events (such as cardiovascular events, respiratory
through compilation of sleep diaries, such as the Pittsburgh Sleep events or illness resulting from immune deficiency).
Diary (Monk 1994).
We planned also to report the quantity and quality of sleep as
measured by objective equipment. In particular, PSG is considered Search methods for identification of studies
the most accurate and objective tool that can be used to measure
sleep and identify sleep disorders (Beecroft 2008). PSG measure-
ments can be analysed to detect sleep onset, sleep efficiency and Electronic searches
length of sleep stages, as well as irregularities, such as apnoea and We identified RCTs through literature searching with systematic
interrupted sleep. However, we planned also to accept measure- and sensitive search strategies as outlined in Chapter 6.4 of the
ments obtained when other tools had been used to record sleep Cochrane Handbook of Systematic Reviews of Interventions (Higgins
activity (Beecroft 2008; Benini 2005; Elliott 2013); ’actigraphy’ 2011). We applied no restrictions to language or publication status.
is a wristband-style tool that measures gross motor activity and is We searched the following databases for relevant trials:
analysed to score total sleep time, sleep efficiency and awakenings; 1. Cochrane Central Register of Controlled Trials
Bispectral Index (BIS) is typically used to calculate depth of anaes- (CENTRAL; 2017, Issue 10);
thesia through interpretation of an EEG reading; and measures 2. MEDLINE (OvidSP, 1946 to 3 October 2017);
of EEG alone can be used to interpret electrical brain activity as 3. Embase (OvidSP, 1974 to 3 October 2017);
sleep time. We acknowledge that collection and interpretation of 4. Cumulative Index to Nursing and Allied Health Literature
data using objective equipment may be problematic in critically ill (CINAHL) (EBSCO, 1937 to 3 October 2017);
people because manual methods having poor inter-rater reliability 5. PsycINFO (EBSCO, 1887 to 3 October 2017).
(Ambrogio 2008). We planned to use interpretations of these mea- We developed a subject-specific search strategy in MEDLINE
surements as reported by each study author to define the quantity and used that as the basis for the search strategies in the other
and quality of sleep. listed databases. The search strategy was developed in consultation
Our aim was to establish not only whether propofol improves sleep with the Information Specialist. Search strategies can be found in
but whether improvement in sleep leads to better patient out- Appendix 1; Appendix 2; Appendix 3; Appendix 4; and Appendix
comes. This is reflected in our secondary outcome measure, which 5.
considered potential physical and psychological consequences of We scanned the following trial registries for ongoing and unpub-
sleep loss, although we acknowledge that it may not be possible to lished trials (2 June 2017):
ascertain whether a reduction in such events is directly attributable 1. World Health Organization International Clinical Trials
to improved sleep. We planned to assess physical consequences of Registry Platform (WHO ICTRP; www.who.int/ictrp/en/);
sleep loss by collecting data from studies that reported the num- 2. International Standard Randomised Controlled Trial
ber of participants who had experienced an adverse event during Number (ISRCTN; www.isrctn.com/);
follow-up, as defined by study authors. We planned to include all 3. ClinicalTrials.gov (clinicaltrials.gov/).
Searching other resources If we identified associated publications from the same study, we
We carried out citation searching of identified included studies planned to create a composite dataset from all eligible publications.
in Web of Science (apps.webofknowledge.com) on 13 June 2017
and conducted a search of grey literature through ’Opengrey’ ( Assessment of risk of bias in included studies
www.opengrey.eu./) on 2 June 2017. We carried out backward
We assessed study quality, study limitations and extent of potential
citation searching of key reviews identified from the searches. We
bias by using the Cochrane ’Risk of bias’ tool (Higgins 2011). We
did not need to contact study authors or organizations.
considered the following domains.
1. Random sequence generation (selection bias).
2. Allocation concealment (selection bias).
Data collection and analysis 3. Blinding of participants and personnel (performance bias).
Two review authors (SL and OSR) independently carried out all 4. Blinding of outcome assessment (detection bias).
data collection and analyses before comparing results and reaching 5. Incomplete outcome data (attrition bias).
consensus. We did not require use of a third review author to 6. Selective outcome reporting (reporting bias).
resolve conflicts. 7. Other sources of bias (e.g. use of concomitant drugs).
Blinding to intervention and control agents may be feasible if
agents are prepared in coded containers, for example, by an inde-
Selection of studies pendent pharmacist; lack of blinding of personnel may introduce
We used reference management software to collate search results risk of bias. Successful blinding of participants to group allocation
and to remove duplicates (Endnote). would be possible and would reduce performance and detection
We used Covidence software to screen results of the search from blinding. It is also feasible that outcome assessors could be blinded
titles and abstracts (Covidence), and identified potentially relevant to group allocation to reduce bias. As participants are critically
studies by using this information alone. We sourced the full texts ill, rates of mortality and withdrawal of consent may be higher in
of all potentially relevant studies and considered whether they met the studies included in this review. Therefore, we paid particular
the inclusion criteria (see Criteria for considering studies for this attention to reasons given for losses, whether losses were related
review). We planned to include abstracts at this stage only if they to the intervention or to chance alone and whether losses were
provided sufficient information and relevant results that included comparable between groups. If participants received concomitant
denominator figures for each intervention or comparison group. medication (e.g. morphine), we considered whether that medica-
We recorded the number of papers retrieved at each stage and tion could affect sleep and whether the concomitant medication
reported this information using a PRISMA flow chart (Liberati was comparable between study groups. We addressed other po-
2009). We reported brief details of closely related papers excluded tential biases in the included studies on an individual basis.
from the review. For each domain, two review authors (SL and OSR) indepen-
dently used one of three measures (low, high or unclear) to judge
whether study authors made sufficient attempts to reduce bias. We
Data extraction and management
recorded this information in the ’Risk of bias’ tables and presented
We used a Cochrane template data extraction form to extract the a summary ’Risk of bias’ figure.
following data from individual studies (Appendix 6).
1. Methods: type of study design; setting; dates of study and
funding sources. Measures of treatment effect
2. Participants: number of participants randomized to each We planned to collect information on adverse events as dichoto-
group; baseline characteristics (to include Acute Physiology and mous data (number of participant events per group). We reported
Chronic Health Evaluation (APACHE) II scores, mechanical the psychological consequences of sleep deprivation as dichoto-
ventilation status and mode of ventilation, length of time in ICU mous or continuous data (e.g. number of participant events per
before study commencement, and concomitant medications). group, mean scores per group on a scale measuring anxiety). We
3. Interventions: details of intervention and comparison anticipated that measures of participant-reported outcomes may
agents (to include dose and timing). differ for each study, depending on the scales used, as may objec-
4. Outcomes: study outcomes as measured and reported by tive measures of quantity and quality of sleep.
study authors (to include types of assessment tools, methods of
data synthesis, units of measure and length of follow-up).
5. Outcome data: results of outcome measures. Unit of analysis issues
We considered the applicability of information obtained from in- If multi-arm studies compared more than one relevant interven-
dividual studies and the generalizability of data to our intended tion versus a control (e.g. no agent), we planned to include both in-
study population (i.e. the potential for indirectness in our review). tervention groups but split the data for the comparison or control
group (using a ’halving’ method), as recommended by Cochrane Data synthesis
Handbook of Systematic Reviews of Interventions (Higgins 2011). We planned to complete meta-analyses of outcomes when com-
parable effect measures were available from more than one study,
Dealing with missing data and only when measures of clinical and statistical heterogeneity
indicated that pooling of results was appropriate. We planned to
We planned to assess whether all measured outcomes had been
use the statistical calculator in Review Manager 5 (RevMan 2014).
reported by study authors by comparing, wherever possible, pub-
We anticipated that our primary outcome of subjective sleep mea-
lished reports with protocols or clinical trial registration docu-
sures would collect data from different sources (participants, car-
ments that had been prospectively published.
ers and personnel). As some evidence suggests that nurses’ assess-
We assessed whether all randomized participants were included
ment of sleep may differ from that of patients (Kamdar 2012b),
in outcome data. We planned to contact authors to request any
we planned not to combine participant-, family- and personnel-
missing outcome data that were not explained. If we were unable
reported assessments of sleep quality but to report these separately.
to obtain these data, we planned to report the data only as they
In addition, we anticipated that subjective sleep assessment tools
were presented in the published report, to include intention-to-
may not be comparable between studies. If sleep assessment tools
treat data. We planned not to combine unexplained incomplete
included categories of sleep assessment, such as no sleep, minimal
data in meta-analysis but to report these data narratively.
sleep, moderate sleep and majority sleep, we planned to split the
We planned to discuss the potential impact of missing data on the
data into dichotomous results by comparing the number of people
finding of our review in the ’Discussion’ section.
reporting moderate and majority sleep versus the number report-
ing minimal and no sleep. We planned to combine data across
Assessment of heterogeneity assessment tools if data could be split into equivalent categories;
We assessed whether our results showed evidence of inconsistency otherwise, we presented a descriptive summary of the results of
by considering heterogeneity. We planned to include all adult ICU each study.
participants with variation in severity of illness, as well as the po- Similarly, we anticipated that our primary outcome of objective
tential for three different comparisons to propofol. Therefore, we sleep assessment may be measured using different tools that were
anticipated likely heterogeneity between studies and assessed clin- not comparable. Unless data were reported with the same tools
ical and methodological heterogeneity by comparing similarities and with the same measurements, such as mean score for BIS or
between participants, interventions and outcomes in our included mean length of each sleep stage for PSG, we presented a descriptive
studies, using information collected during the data extraction summary of the results of each study.
phase. We planned to complete meta-analyses only for studies that For dichotomous outcomes, we planned to calculate the odds ratio
were clinically and methodologically similar. by using summary data presented for each trial. We planned to use
We planned to assess statistical heterogeneity by calculating the the Mantel-Haenszel effects model, unless events were extremely
Chi2 or the I2 statistics. We planned to judge an I2 statistic above rare (one per 1000), in which case we planned to use Peto (Higgins
60% and a Chi2 P value of 0.05 or less to indicate moderate to 2011). For continuous outcomes, for example, PSG readings, we
substantial statistical heterogeneity (Higgins 2011). planned to use mean differences. We planned to use a random-
As well as looking at statistical results, we planned to consider point effects statistical model, which allows for the assumption that in-
estimates and overlap of confidence intervals (CIs). If CIs over- cluded studies may estimate different, but related, intervention
lap, then results are more consistent. However, combined stud- effects.
ies may show a large consistent effect with significant heterogene- We planned to conduct separate analyses for each comparison type
ity. Therefore, we planned to interpret heterogeneity with caution (i.e. propofol versus no agent, propofol versus a different dose of
(Guyatt 2011a). the same agent and propofol versus a different agent).
We planned to calculate 95% CIs and to use a P value of 0.05 or
below to judge whether a result was statistically significant.
Assessment of reporting biases We planned to consider whether results of analyses were imprecise
We attempted to source published protocols for each of our in- by assessing the CI around an effect measure; a wide CI would
cluded studies by using clinical trials registers. We compared the suggest a higher level of imprecision in the results. Inclusion of a
published protocol of one study with published study results to small number of studies may also reduce precision (Guyatt 2011b).
assess the risk of selective reporting bias (Kondili 2012).
If we identified sufficient studies (i.e. more than 10 studies) (
Higgins 2011), we planned to generate a funnel plot to assess Subgroup analysis and investigation of heterogeneity
risk of publication bias in the review; an asymmetrical funnel plot We planned to assess possible reasons for heterogeneity by per-
may indicate potential publication of only positive results (Egger forming subgroup analyses. We planned to consider the severity
1997). of the condition of participants in each study; participants with
a more severe condition may already be subject to increased sleep form the GRADE process (see Data extraction and management,
disruption. Similarly, we planned to consider whether participants Assessment of risk of bias in included studies, Assessment of
had a different outcome according to mechanical ventilation sta- heterogeneity, Assessment of reporting biases and Data synthesis).
tus during the study period. We planned to consider the age of This approach provides an overall measure of how confident we
participants; older people (aged over 65 years) have an altered can be that our estimate of effect is correct (Guyatt 2008).
sleep pattern, which includes increased difficulty falling asleep with We used the principles of the GRADE system to provide an overall
more awakenings and shorter total sleep time (Ancoli-Israel 2009); assessment of evidence related to each of the following outcomes.
therefore, data on sleep outcomes may be different for members 1. Quantity and quality of sleep as measured through reports
of this age group than for younger people. In summary, planned of participants or family members or by personnel assessments.
subgroups were: 2. Quantity and quality of sleep as measured by PSG,
1. severity of the health condition based on APACHE II scores actigraphy, BIS or EEG.
(Knaus 1985) (or comparable severity measures): APACHE II 3. Anxiety or depression, or both.
scores less than 25, 25 to 35, greater than 35; 4. Adverse events (such as cardiovascular events, respiratory
2. mechanically ventilated participants versus participants not events or illness resulting from immune deficiency).
mechanically ventilated; Two review authors (SL and AS) independently used GRADEpro
3. participants aged 65 years or older versus participants software (available at www.guidelinedevelopment.org/) to create
younger than 65 years; and a ’Summary of findings’ table for each comparison. We planned
4. participants in a surgical ICU versus participants in a to reach consensus and resolve disagreements by consulting with
medical ICU. a third review author (PA) if required.
Sensitivity analysis
We planned to explore potential effects of decisions made as part
of the review process as follows. RESULTS
1. Exclusion of studies that we judged to be at high or unclear
risk of selection bias.
2. Use of the alternate meta-analytical effects (fixed-effect or Description of studies
random-effects) model.
We planned to compare effect estimates from the above results
versus effect estimates from the main analysis. We planned to
Results of the search
report differences that altered interpretation of effects.
We planned to perform sensitivity analyses on all outcomes. We screened 17,003 titles and abstracts from database searches,
results from clinical trials register searches, grey literature searches,
and forward and backward citation searches. We carried out full-
’Summary of findings’ table and GRADE text review of 17 articles. We excluded 10 studies, and reported
The GRADE approach incorporates assessment of indirectness, details of two of these excluded studies. We identified four eligible
study limitations, inconsistency, publication bias and impreci- studies, and two studies are awaiting classification. We identified
sion. We used assessments made during our analysis to in- one ongoing study. See Figure 1.
Figure 1. Study flow diagram.
(Engelmann 2014); 10 pm to 7 am Kondili 2012); and 10 pm to
Included studies
6 am (McLeod 1997; Treggiari-Venzi 1996).
We included four studies with 149 participants (Engelmann 2014; Study authors reported administration of a starting bolus of 0.01
Kondili 2012; McLeod 1997; Treggiari-Venzi 1996). mg/kg to 0.05 mg/kg over two minutes (Kondili 2012), and 0.2
Three of the four studies used a parallel design (Engelmann 2014; mg/kg to 0.3 mg/kg over two minutes (Treggiari-Venzi 1996).
McLeod 1997; Treggiari-Venzi 1996). The fourth study used a Engelmann 2014 provided a specific dose for the infusion (2 mg/
cross-over design (Kondili 2012). kg/hour) and other reports stated that propofol was given at a rate
to maintain a given level of sedation (0.3 mg/kg/hour to 3 mg/kg/
Study population and setting
hour in Treggiari-Venzi 1996 but dose was not reported in Kondili
2012 or McLeod 1997).
The four included studies enrolled adults admitted to the ICU.
One study used a cross-over design over two consecutive nights
One study specified inclusion of only participants that were me-
with participants given propofol or no agent on each night
chanically ventilated (Kondili 2012), one study included only
(Kondili 2012). Other studies were for a duration of one night
participants that were not mechanically ventilated (Engelmann
(Engelmann 2014), two nights (McLeod 1997), and five nights
2014), and the remaining two studies did not clearly specify
(Treggiari-Venzi 1996).
whether participants were mechanically ventilated. Three studies
used the APACHE II scoring system to classify the severity of par-
ticipants; Kondili 2012 reported a median (range) APACHE II of Comparisons
23 (16 to 34), McLeod 1997 reported a median (range) APACHE One study compared propofol with no agent (Kondili 2012). One
II in the intervention group of 18 (6 to 35) and in the compari- study compared a higher dose of propofol at night (described as
son group of 17 (6 to 37), Treggiari-Venzi 1996 reported a mean “additional night sedation”) versus a lower dose given throughout
(standard deviation; range) APACHE II in the intervention group the day and maintained overnight (described as “constant light se-
of 13.5 (± 4.5; 8 to 20) and in the comparison group of 14.5 (± dation”) (McLeod 1997). Two studies compared propofol versus
4.1; 9 to 21). Engelmann 2014 reported no scoring system to clas- a benzodiazepine; flunitrazepam (Engelmann 2014), and midazo-
sify the severity of participant conditions. We noted differences in lam (Treggiari-Venzi 1996).
these scores which could reflect severity of participant conditions
between studies.
Participant admission diagnoses included trauma, and postsurgical Measured outcomes
patients (McLeod 1997; Treggiari-Venzi 1996), and only surgical Sleep quality was assessed using standardized patient sleep diaries
patients Engelmann 2014). One study did not report admission (Engelmann 2014) and questionnaires (Treggiari-Venzi 1996).
diagnoses (Kondili 2012). We noted differences in study exclu- McLeod 1997 reported on quantity and quality of sleep by com-
sion criteria; two studies excluded people with renal impairment parison of Ramsay sedation scores by personnel. Two studies re-
(Engelmann 2014; McLeod 1997), two studies excluded people ported on the quantity and quality of sleep as measured using BIS
with neurological disorders (Kondili 2012; Treggiari-Venzi 1996), and PSG (Engelmann 2014; Kondili 2012). Treggiari-Venzi 1996
one study excluded people with head trauma (Treggiari-Venzi assessed psychological consequences of sleep deprivation by con-
1996), and one study excluded people with sepsis (Kondili 2012). sidering participant anxiety and depression.
Two studies reported use of morphine, if required, during the
study period (McLeod 1997; Treggiari-Venzi 1996); we noted that
Excluded studies
morphine use was balanced between participants in each group.
One study reported no opioid use during the study period, with use We assessed the full-texts of 10 studies that did not meet the review
of non-steroidal anti-inflammatory drugs (NSAIDs) if required criteria. We reported two articles (of the 10 studies) in the review
(Kondili 2012). One study reported prior use of benzodiazepines (Seymour 2012; Wu 2016). One study was a cohort study of
and propofol as part of general anaesthesia management in surgical mechanically ventilated patients in the ICU that studied whether
patients, and reported no use of antidepressants or neuroleptics doses of benzodiazepine and propofol were increased at night-
(Engelmann 2014); opioid use was not reported in this study. time and the effect of daytime and night-time use of delirium,
coma and duration of mechanical ventilation (Seymour 2012).
One study was an RCT of non-mechanically ventilated elderly
Interventions (aged 65 years or older) patients in the ICU that studied the effect
All studies reported administration of propofol in the evening to of dexmedetomidine versus a placebo on sleep architecture (Wu
promote sleep. Times of administration were: 11 pm to 6 am 2016). See Characteristics of excluded studies table.
Studies awaiting classification Ongoing studies
We identified one ongoing study (Hollinger 2017). This study
aims to compare propofol with dexmedetomidine administered at
Two studies are awaiting classification (Guo 2012; night-time to promote a circadian rhythm. Participants are in the
NCT00826553). ICU with a diagnosis of delirium, and the study hypothesis is that
We identified one study in database searches which requires trans- reinstituting a normal day-night cycle will decrease the duration
lation; we await translation of the full report before assessing eligi- of delirium. See Characteristics of ongoing studies table.
bility (Guo 2012). We identified one study in searches of clinical
trials registers which had been terminated early due to low accrual
rates; we await publication of the results of this study before as-
Risk of bias in included studies
sessing eligibility (NCT00826553). See Characteristics of included studies table. See ’Risk of bias’
See Characteristics of studies awaiting classification table. graph and ’Risk of bias’ summary (Figure 2; Figure 3).
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study. Note: blank spaces indicate outcome measures that are not reported by study authors
Allocation
in Treggiari-Venzi 1996 and McLeod 1997; the drugs were given
All studies reported that participants were randomly assigned to by the same method (i.e. intravenous infusion over the same time
groups. No studies provided sufficient details of randomization or length), but doses and sedative aims differed between the interven-
methods to conceal allocation from personnel, and we judged all tion and comparison group. Attempts to blind personnel would
studies to have unclear risk of selection bias. require deliberate manipulation of study methodology which was
not reported in either study; we assumed that study investigators
made no attempts to blind personnel. We judged all studies to
Blinding have high risk of performance bias amongst personnel.
It was not possible to blind personnel in Engelmann 2014 (agents Two studies included participant-reported outcomes (Engelmann
given by a different method), or in Kondili 2012 (no agent as 2014; Treggiari-Venzi 1996), and blinding of participants to the
intervention group was particularly relevant. Treggiari-Venzi 1996
comparator). Blinding of personnel was possible but problematic
described an “open” study and therefore participants were not listed in the registration documents and we judged this study to
blinded to their treatment group. We judged this study to have have low risk of reporting bias. We identified no clinical trials
high risk of performance bias amongst participants. Engelmann registration documents for the remaining studies and it was not
2014 reported that participants were unaware of which agents they feasible to judge risk of reporting bias.
were given, and we judged this to have low risk of performance
bias amongst participants.
Two studies reported participant-reported outcomes using sub- Other potential sources of bias
jective measures (Engelmann 2014; Treggiari-Venzi 1996). Par- Two studies reported additional administration of morphine to
ticipants in Treggiari-Venzi 1996 were aware of group allocation participants if required (McLeod 1997; Treggiari-Venzi 1996). Use
and we judged this study to have high risk of detection bias for of morphine between intervention groups was comparable and we
these subjective measures. Participants in Engelmann 2014 were believed it introduced no risk of bias. One study reported that
blinded to the intervention and we judged this study to have low additional opioids were administered to no participants (Kondili
risk of detection bias for the participant-reported outcome. 2012) and we judged this to have low risk of bias. We noted no
Three studies reported measures of sleep using validated measure- details in use of concomitant drugs in Engelmann 2014 and were
ment tools, which rely on objective measures (Engelmann 2014; unable to assess if additional bias had been introduced through
Kondili 2012; McLeod 1997). We judged Kondili 2012 to have concomitant drug use.
low risk of detection bias because outcome assessments were not We noted no differences in baseline characteristics between groups
physicians who had administered propofol. We judged McLeod in parallel design studies (Engelmann 2014; McLeod 1997;
1997, in which assessors made judgements of participants’ diurnal Treggiari-Venzi 1996).
sleep pattern against the Ramsay Sedation Scale, to have low risk
of detection bias because study authors reported that all investi- Effects of interventions
gators were blinded to group allocation. Study authors provided
no detail in Engelmann 2014 and it was not possible to detection See: Summary of findings for the main comparison Propofol for
bias for objective measures and we judged this to have an unclear the promotion of sleep in the intensive care unit versus no agent;
risk of bias. Summary of findings 2 Propofol for the promotion of sleep in
We did not assess performance bias for participants in Kondili the intensive care unit versus propofol at a different rate or dose;
2012 and McLeod 1997 because participant-reported outcomes Summary of findings 3 Propofol for the promotion of sleep in the
were not assessed in these studies and we did not believe that blind- intensive care unit versus another agent specifically administered
ing would influence sleep as measured with objective measures. to promote sleep in the intensive care unit
Similarly, we did not assess risk of detection bias for objective mea- We noted differences between study designs in methods and types
sures in Treggiari-Venzi 1996, as this study did not report such of comparative agents. We did not combine data in meta-analysis.
outcomes.
Comparison 1: propofol versus no agent
Incomplete outcome data One study compared propofol with no agent (Kondili 2012).
We noted a large number of losses in Engelmann 2014, and tech-

nical difficulties during the study also reduced available data; we Primary outcomes
judged this study to have high risk of attrition bias. Study authors
reported a large number of losses in Treggiari-Venzi 1996 and
included explanations; we were concerned that reasons for losses 1. Quantity and quality of sleep as measured through reports
could be described as ’not missing at random’ (i.e. some partic- of participants or family members or by personnel
ipants lost due to reactions against midazolam) and lack of data assessments
for these participants could have influenced results. We judged Kondili 2012 did not report this outcome.
Treggiari-Venzi 1996 to have high risk of attrition bias.
We noted no risk of bias in the loss of one participant in McLeod
1997, and in Kondili 2012; we judged both studies to have low 2. Quantity and quality of sleep as measured by PSG,
risk of attrition bias. actigraphy, BIS or EEG
Kondili 2012 (13 randomized participants) used PSG to assess this
outcome. Study authors reported no statistically significant differ-
Selective reporting ences in the total sleep time between groups given propofol ver-
We identified prospective clinical trials registration for one study sus no propofol, or in the percentage of sleep efficiency. Although
(Kondili 2012); outcomes in the study report reflected outcomes all participants had an abnormal sleep architecture, study authors
reported no statistically significant differences in total sleep time Ramsay Sedation Scale to assess the effectiveness of an increased
at Stage 1, Stage 2, and slow wave sleep depending on whether dose of propofol on diurnal rhythm over two nights. All partici-
propofol had been administered. However, study authors noted pants were given propofol during daytime hours at a level of two
that propofol significantly disrupted REM sleep (P = 0.04), with to three on the Ramsay scale (constant light sedation) as standard
only one participant in the propofol group experiencing REM treatment for their condition. However, the intervention group
sleep. Study authors concluded that propofol did not improve was given additional propofol in the evening with the aim of
sleep quality in the ICU and promoted further disruption by ob- achieving a depth of four or five on the Ramsay scale (with a pa-
structing the usual REM in sleep architecture. See Table 1. tient sleeping but still rousable) whilst the control group contin-
We used the GRADE approach and assessed the quality of ev- ued to receive constant light sedation. Study authors reported that
idence for this outcome to be very low. We noted a high level some sleep rhythms for participants at either end of the spectrum
of performance bias and downgraded by one level. We identified of severity of condition appeared to be unaffected by the differ-
sparse data for this outcome, which reduced the precision of the ent propofol administration aims. However, the study authors re-
result and we downgraded an additional two levels. See Summary ported that they were able to achieve a successful diurnal rhythm
of findings for the main comparison. in nine of the participants in the intervention group compared to
three participants in the control group. Study authors reported that
an increased dose of propofol led to greater sedation rhythmicity.
Secondary outcomes
We noted that this study did not conclude whether the ’sedation
rhythmicity,’ which follows a typical night and day structure, was
directly equivalent to ’sleep’. See Table 2.
1. Anxiety or depression, or both, as measured using
We used the GRADE approach and assessed the quality of the
validated tools
evidence for this outcome to be very low. We noted a high level
Kondili 2012 did not report data for anxiety or depression. of performance bias and downgraded by one level. We were con-
cerned about the use of a sedation scale, typically used to assess
2. Adverse events (such as cardiovascular events, respiratory anaesthesia, rather than a sleep scale and downgraded by one level
events or illness resulting from immune deficiency) for indirectness. We identified sparse data for this outcome which
reduced the precision of this result and we downgraded by one
Kondili 2012 did not report data for adverse events.
level for imprecision. See Summary of findings 2.
Subgroup analysis
We did not perform a subgroup analysis because there were too 2. Quantity and quality of sleep as measured by PSG,
few studies to conduct meta-analysis. actigraphy, BIS or EEG
McLeod 1997 did not report data for this outcome.
We did not perform a sensitivity analysis because there were too
Secondary outcomes
few studies to conduct meta-analysis.
Comparison 2: propofol versus propofol at a different

1. Anxiety or depression, or both, as measured using
rate or dose
validated tools
One study compared a higher dose of propofol at night versus a
lower dose given throughout the day and maintained overnight McLeod 1997 did not report data for this outcome.
(McLeod 1997).
2. Adverse events (such as cardiovascular events, respiratory

Primary outcomes events or illness resulting from immune deficiency)
McLeod 1997 did not report data for adverse events.
1. Quantity and quality of sleep as measured through reports
of participants or family members or by personnel
assessments Subgroup analysis
McLeod 1997 (30 randomized participants) reported an assess- We did not perform a subgroup analysis because there were too
ment of sleep conducted by personnel. Study authors used the few studies to conduct meta-analysis.
Sensitivity analysis 2. Quantity and quality of sleep as measured by PSG,
We did not perform a sensitivity analysis because there were too actigraphy, BIS or EEG
few studies to conduct meta-analysis. Engelmann 2014 (66 randomized participants) used BIS moni-
toring to assess sleep quality and quantity. In this study, the me-
dian BIS values differed with significantly lower values reported
Comparison 3: propofol versus another agent, in those participants given propofol compared to those given flu-
administered specifically to promote sleep nitrazepam (overall median BIS 74.05 with propofol and median
Two studies compared propofol versus a benzodiazepine; fluni- BIS 78.7 with flunitrazepam, P = 0.016). However, the BIS values
trazepam (Engelmann 2014), and midazolam (Treggiari-Venzi were also reported over time for the first five hours after the start of
1996). the intervention. This demonstrated that the effect of a single bo-
lus dose of flunitrazepam had a reduced sedative effect over time,
with BIS values starting at 72.05 in the first hour and increasing
Primary outcomes at each hour to 81.00 in the fifth hour. Of note, BIS values were
significantly lower in the flunitrazepam group in the first hour (P
= 0.01) but at all other time points values were significantly lower
1. Quantity and quality of sleep as measured through reports in the propofol group. Engelmann 2014 looked at fluctuations in
of participants or family members or by personnel BIS values for individual participants. Basing interpretation of BIS
assessments values on those given by Sleigh 1999, who linked ranges of BIS
Engelmann 2014 (66 randomized participants) assessed sleep values to light sleep, slow wave sleep and REM sleep, Engelmann
quality with an amended version of the Pittsburgh Sleep Diary, 2014 reported that participants spent significantly longer time in
asking participants to judge aspects of sleep quality on a numer- deep sleep when they were given propofol and participants in the
ical scale. Study authors reported fewer awakenings and reduced flunitrazepam group had more light and REM sleep. Participants
duration of awakenings in the propofol group. Study authors re- in the flunitrazepam group also had significantly more arousals
ported that total sleep duration was similar. We noted that partic- from sleep (defined as awakenings of less than three minutes). The
ipants were blinded to group allocation in this study; participants study authors interpreted this collection of data as demonstrating
assessed an improvement in sleep quality, and an improvement in that propofol improved the overall quality of sleep in the ICU. See
regeneration and refreshment after sleep when given propofol. Table 3.
Treggiari-Venzi 1996 (40 randomized participants) used HADS We used the GRADE approach and assessed the quality of the
to assess the quality of sleep experienced by participants. Study evidence for this outcome to be very low. We noted a high level
authors collected scores on days one, three and five of the study of performance bias and downgraded by one level. We identified
period. Study authors reported an improvement in sleep quality sparse data and downgraded by two levels for imprecision. The
over time which was not significant; they concluded that there use of BIS to measure quality and quantity of sleep may not be
was no significant difference in sleep quality. We noted that study an appropriate and direct measurement tool for this outcome; we
authors stated that “the first five items of the HADS evaluate the downgraded by one level for indirectness. See Summary of findings
quality of sleep, the degree of restlessness, dreams or nightmares 3.
and memories about the night-time.” The study authors reported
no additional details and we were unable to ascertain how ’quality Secondary outcomes
of sleep’ could be measured using the standard published HADS,
which is typically only a measure of anxiety and depression; there-
fore, we were concerned about the validity and reliability of the 1. Anxiety or depression, or both, as measured using
tool that was used for this outcome. validated tools
See Table 3. Treggiari-Venzi 1996 (40 randomized participants) aimed to anal-
We used the GRADE approach and assessed the quality of the yse levels of anxiety and depression in patients in the ICU and
evidence for this outcome to be very low. We noted a high level used the HADS. This questionnaire requires participants to score
of performance bias in the studies and downgraded by one level. 14 statements from zero to three with a maximum score of 21.
Outcome data were not consistent between studies and we down- Study authors reported that participants were asked to score the
graded one level for inconsistency. We were concerned about the questionnaire at noon after the first, third and fifth night. Results
validity of the measurement tool in Treggiari-Venzi 1996 when showed high levels of anxiety in many participants in both groups
used as a measure of sleep quality and we downgraded by one level (scoring greater than 10 on the HADS, which signifies severe levels
for indirectness. We identified sparse data for this outcome and we of anxiety). However, study authors noted that mean scores did
downgraded one level for imprecision. See Summary of findings not differ significantly between groups on each of the three days
3. of measurement.
Study authors in Treggiari-Venzi 1996 also reported abnormal tified only one study for this outcome and we downgraded the
levels of depression in both groups (scoring greater than 10). No evidence by two levels for imprecision. See Summary of findings
participant experienced a new onset of depressive state in either 3.
group and study authors noted no significant differences between
groups on each of the three days of measurement.
These results show that patients in the ICU have abnormally high 2. Adverse events (such as cardiovascular events, respiratory
levels of anxiety and depression. However, study authors provided events or illness resulting from immune deficiency)
no evidence that propofol given to promote sleep improved levels Engelmann 2014 and Treggiari-Venzi 1996 did not report adverse
of anxiety and depression whilst in the ICU. events.
See Table 3.
We used the GRADE approach and assessed the quality of evi-
Subgroup analysis
dence for this outcome to be very low. We were concerned about
the study limitations, in particular the high risk of performance We did not perform a subgroup analysis because there were too
and detection bias from unblinded participants, which could in- few studies to conduct meta-analysis.
fluence the results. The magnitude and direction of this effect may
depend on what participants may know or have been told about
propofol and midazolam and, although the study authors reported
no difference between results, it was unclear whether this result We did not perform a sensitivity analysis because there were too
was influenced by bias. We downgraded this by one level. We iden- few studies to conduct meta-analysis.
Propofol for the promotion of sleep in adults in the intensive care unit (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Propofol for the promotion of sleep in the intensive care unit versus propofol at a different rate or dose

Settings: intensive care unit, UK
Comparison: propof ol at a dif f erent rate or dose

(studies) (GRADE)
Quantity and quality of sleep as Outcom e m easured using Ram - 30 (1 study) ⊕ We identif ied only 1 study and could
measured through reports of par- say Sedation Scale. Study authors Very low1 not conduct m eta-analysis
ticipants or family members or reported that m ore participants
by personnel assessments who were given a higher dose of
Data collected at end of study propof ol had a successf ul diurnal
f ollow-up rhythm , and achieved a greater
sedation rhythm icity
Quantity and quality of sleep as Not reported. - - -

measured by PSG, actigraphy,
BIS or EEG
f ollow-up
Anxiety or depression, or both, as Not reported. - - -

measured using validated tools
f ollow-up
Adverse events (such as car- Not reported. - -

immune deficiency)
BIS: Bispectral Index; EEG: electroencephalogram ; PSG: polysom nography.

20

1 High
level of perf orm ance bias; downgraded by one level. Concern about use of a sedation scale rather than a sleep scale;
downgraded by one level f or indirectness. One study, with f ew participants; downgraded one level f or im precision.
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
21
Propofol for the promotion of sleep in the intensive care unit versus another agent specifically administered to promote sleep in the intensive care unit

Settings: intensive care units in Germ any and Switzerland
Comparison: another agent specif ically adm inistered to prom ote overnight sleep

(studies) (GRADE)
Quantity and quality of sleep as Outcom e m easured by dif f erent 106 (2 studies) ⊕ We did not conduct a m eta-analysis
measured through reports of par- m ethods in each study (Pitts- Very low1 because studies dif f ered in types of
ticipants or family members or burgh Sleep Diary; Hospital Anxi- m easurem ent tools
by personnel assessments ety and Depression Scale)
Data collected at end of study 1 study reported that participants
f ollow-up given propof ol had f ewer awaken-
ings, reduced duration of awaken-
ings and sim ilar total sleep dura-
tion. 1 study reported no evidence
of a dif f erence in sleep quality
Quantity and quality of sleep as Outcom e m easured by BIS. 66 (1 study) ⊕ We identif ied only 1 study and could
measured by PSG, actigraphy, 1 study reported that participants Very low2 not conduct a m eta-analysis
BIS or EEG given propof ol had longer tim e in
Data collected at end of study deep sleep, with f ewer arousals
f ollow-up f rom sleep
Anxiety or depression, or both, as Study authors reported high levels 40 ⊕ We identif ied only 1 study and could
measured using validated tools of anxiety and depression in both (1 study) Very low3 not conduct a m eta-analysis
Data collected at end of study participant groups, and no evi-
f ollow-up dence of a dif f erence with those
given propof ol
22
Adverse events (such as car- Not reported. - - -

immune deficiency)
BIS: Bispectral Index; EEG: electroencephalogram ; PSG: polysom nography.

1
High level of perf orm ance bias in studies; downgraded by one level. Outcom e data were not consistent between studies;
downgraded one level f or inconsistency. Concern about validity of m easurem ent tool in Treggiari-Venzi 1996; downgraded
by one level f or indirectness. Lim ited num ber of studies, with f ew participants; downgraded one level f or im precision.
2 High level of perf orm ance bias; downgraded by one level. Data f rom single study with f ew participants; downgraded by two
levels f or im precision. Use of BIS to m easure quality and quantity m ay not be appropriate, and m ay not provide a direct
m easurem ent, f or this outcom e; downgraded by one level f or indirectness.
3
High level of perf orm ance bias in studies; downgraded by one level. Data f rom single study with f ew participants; downgraded
two levels f or im precision.
23
DISCUSSION There had been some attempts to reduce detection bias within
studies but there were a high number of losses in two of the stud-
ies. These biases provided limitations to the review outcomes. We
Summary of main results were also concerned about precision in the data, and heterogeneity
between studies in terms of design, comparative agents and par-
We identified four RCTs with 149 participants. We identified two
ticipant groups. Two studies reported a large number of losses and
studies awaiting classification (one requires translation to English
we judged these to have high attrition bias that could influence
and one is listed as completed in a clinical trial register but not yet
their results.
published) and one ongoing study.
Despite evidence about sleep disturbance in the ICU, we identified
One study compared propofol versus no agent. Study authors mea-
only a small number of RCTs with few participants. No studies
sured quantity and quality of sleep using PSG and reported no
reported a power calculation and we expected that they were not
evidence of a difference in duration of sleep or sleep efficiency, and
sufficiently powered to produce a meaningful result; as quantity
reported disruption to usual REM with propofol.
and quality of sleep may vary widely in the healthy population, we
One study compared different doses of propofol. Study authors
anticipate that a large number of critically ill participants would
measured quantity and quality of sleep using the Ramsay Sedation
be required to account for normal variation.
Scale and reported that more participants who were given a higher
We noted that included studies were conducted over a short time.
dose of propofol had a successful diurnal rhythm, and achieved a
Length of stay in the ICU differs depending on illness severity;
greater sedation rhythmicity.
however, it is reasonable to assume that the use of propofol for only
Two studies compared propofol versus a benzodiazepine (fluni-
one night would be insufficient to reduce the long-term impact
trazepam, one study; midazolam, one study). Study authors mea-
of sleep deprivation such as on levels of anxiety and depression.
sured quantity and quality of sleep using the Pittsburgh Sleep
Study authors measured participant self-reports of sleep quality
Diary and HADS. One study reported fewer awakenings of re-
and quantity immediately after administration of the intervention.
duced duration with propofol, and similar total sleep time between
It would be most appropriate to ask a healthy person to reflect on
groups, and one study reported no evidence of a difference in sleep
quality of sleep during the following morning; however, critically
quality. One study comparing propofol with flunitrazepam mea-
ill people may have limited communication to discuss perception
sured quantity and quality of sleep with BIS and reported longer
of quality of sleep. Participant-reported outcomes for sleep studies
time in deep sleep, with fewer arousals. One study comparing
in critically-ill people may benefit from a longer follow-up period.
propofol with midazolam reported higher levels of anxiety and
Patients in the ICU may be constantly sedated, and propofol is
depression in both groups, and no evidence of a difference when
a popular anaesthetic agent for long-term sedation. We included
participants were given propofol.
one study that attempted to use different doses of propofol for
daytime and night-time sedation. This study measured sleep using
the Ramsay Sedation Scale, which is designed to measure depth
Overall completeness and applicability of of anaesthesia rather than to assess depth of sleep. Also, we in-
evidence cluded a study that used BIS monitoring to quantify sleep, which
Included studies recruited critically ill participants in the ICU involves equipment designed to measure depth of anaesthesia. We
and administered propofol in appropriate doses to promote sleep. are uncertain whether these are appropriate to measure the review
However, we noted differences between participants such as the outcomes, and we believed that these measurement tools may also
severity of participant condition measured with APACHE II, and impact on the quality of the evidence.
whether participants were mechanically ventilated. We noted dif-
ferences in exclusion criteria, for example, one study excluded peo-
ple with sepsis and one study excluded people with head injury.
Potential biases in the review process
Also, study designs differed and participants in some studies were
not sedated during the day; this would suggest participants were We conducted this review using Cochrane methodology, using
less ill than within studies in which participants were given con- two authors at each of the review process to minimize bias ac-
stant sedation. We believe that this heterogeneity compromises cording to our published protocol (Lewis 2016). We conducted a
the generalizability and applicability of these results to the general thorough search that included clinical trials registers, forward and
ICU population. backward citation tracking, and grey literature. Two studies are
awaiting classification (Guo 2012; NCT00826553); not incorpo-
rating these studies may affect the review findings.
Quality of the evidence
No study authors had provided adequate description of the ran-
domization process and all were at high risk of performance bias. Agreements and disagreements with other
studies or reviews Implications for research
Data on measurement of sleep in the ICU were limited and we Large randomized controlled trials which include a general ICU
are aware of no other reviews on the use of propofol in the ICU. adult population would provide more certainty for this review.
The findings in Engelmann 2014 were comparable to those in Currently, PSG is the most appropriate objective measurement of
the study by Murphy 2011 which reported an increase of slow sleep and using this equipment would ensure consistent sleep mea-
wave sleep with propofol. However, these findings contradicted surement across future studies. However, measurement of sleep
Kondili 2012, which reported no increase in slow wave sleep with quality can be subjective and blinding of participants is essential
propofol. Murphy 2011 did not measure REM sleep, and we are for unbiased participant-reported measurement of sleep quality
unaware of any other studies that measure this. and quantity. We would recommend that future studies include
methods to reduce performance and detection bias by personnel
and study investigators. Study design should consider increasing
the time of propofol administration for more than one or two
nights, and including longer follow-up time points.
AUTHORS’ CONCLUSIONS
Implications for practice ACKNOWLEDGEMENTS

We found insufficient evidence to determine whether admin- We would like to thank Nicola Petrucci (Content Editor); Asieh
istration of propofol would improve the quality and quantity Golozar (Statistical Editor); and Katrine B Buggeskov, Angela
of sleep in adults in the intensive care unit (ICU). We identi- Jerath and Russel J Roberts (Peer Reviewers) for help and edi-
fied four studies with few participants. We noted differences in torial advice provided during preparation of the protocol (Lewis
study designs, methodology, comparative agents and illness sever- 2016) for the systematic review. We would like to thank Nicola
ity amongst study participants. We did not pool data and we used Petrucci (Content Editor); Jing Xie (Statistical Editor); Katrine
the GRADE approach to downgrade the certainty of our evidence B Buggeskov, Andrew MacDuff and Angela Jerath (Peer Review-
to very low. Two studies are awaiting classification (Guo 2012; ers); Janet Wale (Consumer Editor); and Jane Cracknell (Manag-
NCT00826553) and one study is ongoing (Hollinger 2017); in- ing Editor) for their help and editorial advice provided during the
corporation of these studies may alter the conclusion of the review. preparation of the systematic review.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Engelmann 2014
Methods RCT.
Parallel design.
Participants Total number of randomized participants: 66.

Setting: ICU in Germany.
Inclusion criteria: patients admitted to the ICU after surgical intervention
Exclusion criteria: patients with pre-existing sedation, mechanical ventilation, renal in-
sufficiency or cerebral diseases
Baseline characteristics
Propofol group:
Gender M/F: 30/4.
Age mean (SD): 60.2 (± 13.0) years.
Bodyweight mean (SD): 84.71 (± 10.78) kg.
BMI mean (SD): 27.42 (± 3.18) kg/m2 .
Flunitrazepam group:
Gender M/F: 28/4.
Age mean (SD): 59.9 (± 11.02) years.
Bodyweight mean (SD): 79.57 (± 10.46) kg.
BMI mean (SD): 25.94 (± 3.18) kg/m2 .
Interventions Propofol group:

n = 34; 1 exclusion because of prolonged length of stay (included in analysis), 3 losses
because of incomplete signal recordings; number analysed with BIS = 31, number anal-
ysed for sleep diary = 34
Details: propofol 20 mg/mL (2 mg/kg/h) administered IV continuously over 7 hours,
from 11 pm to 6 am
Flunitrazepam group:
n = 32; 7 losses because of incomplete signal recordings, number analysed with BIS =
25, number analysed for sleep diary = 32
Details: flunitrazepam 0.015 mg/kg administered as an IV bolus over 2 minutes
Outcomes Quantity of sleep as evaluated with EEG and BIS; quality of sleep as evaluated with
participant sleep diaries (Pittsburgh Sleep Diary (PghSD))
Notes Funding/declarations of interest: departmental funding.

Study dates: not reported.
Note: attempts made to reduce environmental impact and disturbances by clinical staff
in the ICU. Records maintained of disruption and reported as equivalent for each par-
ticipant in each group
Note: 59 participants were pretreated (for surgical procedures) within 48 hours of study
inclusion with benzodiazepines and propofol: study authors did not report the balance
between groups. 4 participants (3 in propofol group; 1 in flunitrazepam group) were
pretreated within 48 hours of study inclusion with benzodiazepines alone
Engelmann 2014 (Continued)
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Study authors reported that participants were randomly assigned
bias) to groups but provided no additional details of randomization
methods
Allocation concealment (selection bias) Unclear risk No details.
Blinding of personnel (performance bias) High risk Study authors provided no details of attempts to blind person-
nel to group allocation. We assumed physicians were aware of
groups allocation because method of drug administration dif-
fered between groups
Blinding of participants (performance bias) Low risk Participants were unaware of which intervention they were given
Blinding: subjective measures (detection Low risk For the participant-reported outcomes of sleep quality, partici-
bias) pants were unaware which intervention they were given
Blinding: objective measures (detection Unclear risk Study authors provided no details of who assessed BIS monitor-
bias) ing and whether assessors were blinded
Incomplete outcome data (attrition bias) High risk Study authors reported a signal loss during outcome assessment
All outcomes for 10 participants. Also, data were only available for 5 out of a
possible 7 hours, due to technical difficulties
Selective reporting (reporting bias) Unclear risk We were unable to source any prepublished protocol or clinical
trials registration documents; therefore, it was not feasible to
judge risk of reporting bias
Other bias Unclear risk Baseline characteristics appeared comparable between groups.
Study authors reported that antidepressants and neuroleptic
agents were not given during the study period, and reported no
detail of other agents (e.g. opioids) given to any participants
during study period; unable to judge whether risk of bias was
introduced through imbalance of concomitant drug use
Kondili 2012
Methods RCT.
Cross-over design.

N = 13; 1 participant was excluded because of severe acidosis; number analysed = 12
Setting: ICU in Greece.
Inclusion criteria: critically ill patients who had been mechanically ventilated for ≥ 48
Kondili 2012 (Continued)
hours and anticipated to be on assisted modes for ≥ 2 consecutive days; patients not
requiring sedation or analgesia with opioids
Exclusion criteria: GCS < 11; APACHE II > 15; presence of delirium; administration of
any sedative drugs or opioids in previous 24 hours; detectable plasma levels of sedative
drugs (e.g. benzodiazepine, propofol) or opioids (e.g. morphine); history of epilepsy
or other neurological disease that may affect quality of sleep; history of sleep apnoea;
ongoing sepsis
(for 12 participants, not divided by group due to cross-over design)
Gender M/F: 6/6.
Age median (IQR): 73 (63-75) years.
APACHE II at admission median (IQR): 23 (16-34).
Interventions Propofol bolus of 0.01-0.05 mg/kg over 2 minutes at 10 pm, followed by IV continuously
until 7 am to maintain Ramsay Sedation Scale level 3
Each participant studied for 2 consecutive nights, with or without propofol, in random
order
Outcomes Quality of sleep measured using PSG (total sleep fragmentation - sum of arousals and
awakenings per hour of sleep; breathing variables and asynchrony)
Notes Funding/declarations of interest: Cretan Critical Care Society (details taken from pub-
lished protocol)
Study dates: October 2009 to October 2011.
Notes: attempts made to reduce other confounders to sleep disruption (single ICU room,
window blinds closed, noise, nursing and other interventions minimized during study
night. Light decreased to minimum level). Attempts to maintain same conditions on
both nights of study
Participants administered NSAIDs for analgesia of required.
Risk of bias
Random sequence generation (selection Unclear risk Study authors reported that participants were randomly as-
bias) signed to groups but provided no additional details of ran-
domization methods
Blinding of personnel (performance bias) High risk Propofol compared to ’no agent’ and therefore not possible
to blind personnel
Blinding: objective measures (detection Low risk Physicians who administered study drug were not given ac-
bias) cess to EEG readings during study
Incomplete outcome data (attrition bias) Low risk Loss of 1 participant who required change of mode of ven-
All outcomes tilation due to severe respiratory acidosis; unlikely to affect
overall outcome data
Kondili 2012 (Continued)
Selective reporting (reporting bias) Low risk Registered trial ID: ISRCTN72847182. Study appeared to
report all outcomes as presented in protocol
Other bias Low risk Study authors reported no opioid use and no sedative use
for any participant, except intervention drugs for overnight
sleep promotion, during the study period. We considered
whether bias was introduced by use of a cross-over design and
whether there was a sufficient washout period after propofol
use; propofol has a rapid offset and we judged that this design
introduced no bias
McLeod 1997
Methods RCT.
Parallel design.

Setting: ICU in UK.
Inclusion criteria: aged > 18 years, expected to be sedated for > 50 hours
Exclusion criteria: patients who had received steroids, history of hyperlipidaemia,
epilepsy, endocrine disease or renal impairment requiring haemodialysis or haemofiltra-
tion or muscle relaxants
Baseline characteristics:
Additional night sedation group:
Age mean (SD): 61.6 (± 10.8) years
Gender M/F: 10/5
Weight mean (SD): 67.6 (± 12.5) kg
APACHE II median (range): 18 (6-35)
Constant light sedation group:
Age mean (SD): 57.4 (± 14.8) years.
Gender M/F: 10/4.
Weight mean (SD): 68.1 (± 13.6) kg.
APACHE II median (range): 17 (6-37).
Interventions All participants given initial background infusion of morphine 2 mg/hour and infusion
of propofol 2% for sedation. Dose of propofol based on assessment of participants on
Ramsay Sedation Scale
Additional night sedation group:
n = 15; no losses.
Details: participants received constant light sedation 6 am to 10 pm. Additional propofol
given 10 pm to 6 am with aim of Ramsay Sedation Scale score 4-5 (“sleeping, but
rousable”)
Constant light sedation group:
n = 15; 1 loss; number analysed = 14.
Details: participants received IV propofol for whole study period (50 hours) with aim
of Ramsay score 2-3
McLeod 1997 (Continued)
Outcomes Presence or absence of diurnal pattern, assessed by 6 investigators. Sedation scores assessed
by ’cosinor’ analysis
Notes Funding/declarations of interest: sponsored by Zeneca Pharmaceuticals

Participants were given additional morphine for analgesia if required
Risk of bias
methods
Blinding of personnel (performance bias) High risk Doses given for different sedative aims and, therefore, not pos-
sible to blind personnel
Blinding: objective measures (detection Low risk All investigators were blinded to group allocation.
bias)
Incomplete outcome data (attrition bias) Low risk Loss of data for 1 participant not explained, but low number
All outcomes unlikely to affect overall result
trials registration documents; therefore, it was not feasible to
judge risk of reporting bias
Other bias Low risk Participants in both groups were given morphine; doses were
comparable between groups. Baseline characteristics appear
comparable
Treggiari-Venzi 1996
Methods RCT.
Parallel design.

Setting: ICU in Switzerland.
Inclusion criteria: conscious, non-intubated patients; aged 18-75 years; expected stay in
the ICU ≥ 5 days
Exclusion criteria: any known neurological disorder, head trauma, long-term therapy
with psychotropic drugs or sedatives, or alcohol abuse
Propofol group:
Treggiari-Venzi 1996 (Continued)
n = 20; 1 loss (because participant was in an extremely anxious state); number analysed
= 19
Age mean (SD): 48 (± 17) years.
Gender: not reported.
APACHE II mean (SD) (range): 13.5 (± 4.5) (8-20).
Midazolam group:
n = 20; 7 losses (5 had reactions to midazolam; 2 discharged from the ICU); number
analysed = 13
Age years mean (SD): 41 (± 16) years.
Gender: not reported.
APACHE II mean (SD) (range): 14.5 (± 4.1) (9-21).

Details: bolus of 0.2-0.3 mg/kg over 2 minutes, followed by continuous infusion at rate
of 0.3-3 mg/kg per hour. Bolus at 10 pm on first night of admission, infusion stopped
at 6 am each day. Study period for 5 days
Midazolam group:
Details: bolus of 0.01-0.07 mg/kg over 2 minutes, followed by continuous infusion at
a rate of 0.03-0.2 mg/kg per hour. Bolus at 10 pm on first night of admission, infusion
stopped at 6 am each day. Study period for 5 days
Infusion rate adjusted in both groups to maintain level of sedation on Ramsay Sedation
Scale of 3-4
Morphine administered IV to all participants to assure adequate pain control (using
visual analogue scale to maintain equivalent levels in each participant)
Outcomes Levels of anxiety and depression.

Quality of sleep, degree of restlessness, dreams/nightmares, memories of night-time
Both assessed using HADS questionnaire at noon after first, third and fifth nights
Notes Funding/declarations of interest: no details.

Note: some exclusions during study (see ’Risk of bias’ table), baseline characteristics only
available for 32 participants
Risk of bias
methods
Blinding of personnel (performance bias) High risk Study authors reported no description of blinding; blinding
would have required deliberate methodological changes and we
assumed no blinding was achieved
Treggiari-Venzi 1996 (Continued)
Blinding of participants (performance bias) High risk Study authors described study as ’open’ label; participants were
not blinded to group allocation
Blinding: subjective measures (detection High risk For the participant-reported outcome of assessment of sleep
bias) quality, participants were aware of group allocation
Incomplete outcome data (attrition bias) High risk High number of losses after randomization: 7 from midazolam
All outcomes group (5 due to reactions against midazolam; 2 discharged from
the ICU); 1 from propofol group
trials registration documents; therefore, it is not feasible to judge
risk of reporting bias
Other bias Low risk Participants in both groups were given morphine; doses were
comparable between groups. Baseline characteristics appeared
comparable
APACHE II: Acute Physiology and Chronic Health Evaluation II; BIS: Bispectral Index; BMI: body mass index; EEG: electroencephalo-
gram; GCS: Glasgow Coma Scale; HADS: Hospital and Depression Anxiety Scale; ICU: intensive care unit; ID: identification;
IQR: interquartile range; IV: intravenous; M/F: men/women; n: number of participants; NSAIDs: non-steroidal anti-inflammatory
drugs; PSG: polysomnography; RCT: randomized controlled trial; SD: standard deviation.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Seymour 2012 Mechanically ventilated adults in the ICU. Aimed to assess whether doses of benzodiazepines and propofol were
increased at night. Cohort study design was ineligible
Wu 2016 RCT. Non-mechanically ventilated elderly (aged 65 years or older) patients in the ICU. Dexmedetomidine given
to promote sleep. Did not include a comparison with propofol
ICU: intensive care unit; RCT: randomized controlled trial.
Characteristics of studies awaiting assessment [ordered by study ID]
Guo 2012
Methods RCT.
Multi-arm parallel design.
Participants Mechanically ventilated patients in the ICU.
Interventions Circadian rhythm vs daily interruption vs continuous sedation or demand sedation
Outcomes Recovering natural circadian rhythm, duration of mechanical ventilation
Notes Limited detail in English abstract. Report requires translation from Chinese before eligibility assessment
NCT00826553
Methods RCT.
Parallel design.
Participants Inclusion criteria: adult patients admitted to the medical ICU who required mechanical ventilation and were sedated
with a GABA agonist, expectation of being mechanically ventilated for > 24 hours
Exclusion criteria: aged < 18 years; pregnant; inability to obtain informed consent from the patient or his or her
surrogate; physiologically benzodiazepine dependent; at risk of withdrawal syndrome, anoxic brain injuries, stroke
or neurotrauma; medical team following patient unwilling to change sedation regimen; moribund and not expected
to survive 24 hours or actively withdrawing medical support; documented allergy to study medications; advanced
heart block at time of screening; prisoners; RASS target ≤ -4 at the time of screening; PSG equipment unavailable
Interventions Dexmedetomidine vs GABA agonist (e.g. propofol, benzodiazepines)
Outcomes Time spent in standard sleep stages (N1, N2, N3, REM), time spent in atypical sleep, presence of burst suppression
Notes Study terminated due to poor recruitment. We await publication of study report to assess eligibility
GABA: gamma-aminobutyric acid; ICU: intensive care unit; N1, N2, N3: stages of sleep; PSG: polysomnography; RASS: Richmond
agitation-sedation scale; RCT: randomized controlled trial; REM: rapid eye movement.
Characteristics of ongoing studies [ordered by study ID]
Hollinger 2017
Trial name or title Comparison of propofol and dexmedetomidine infused overnight to treat hyperactive and mixed ICU delir-
ium: a protocol for the Basel ProDex clinical trial
Methods RCT.
Parallel design.
Hollinger 2017 (Continued)
Participants Target number of randomized participants: 316.

Setting: adult ICU admitting medical or surgical patients, Switzerland
Inclusion criteria: adult patients aged > 18 years, current delirium (hyperactive or mixed type) detected by a
specialized assessment method (ICDSC) in 1 of participating ICUs
Exclusion criteria: delirium prior to ICU admission, egg and soy allergy, hypersensitivity to the active sub-
stances, advanced heart block (grade 2 or 3) unless paced, bradycardia of different origin, uncontrolled hy-
potension, acute cerebrovascular conditions, severe cardiac dysfunction, aged < 18 years, terminal state, preg-
nancy, status epilepticus or postictal states following seizures on EEG, active psychosis, delirium tremens,
substance abuse with experience of acute withdrawal

Propofol 1% (1 g/100 mL) 1-4 mg/kg/hour administered by continuous IV infusion from 8 pm to 6 am
beginning the evening after diagnosis of hyperactive or mixed delirium
Dexmedetomidine group:
Details: dexmedetomidine (200 µg/2 mL) 0.7 µg/kg bolus, following by 1.4 µg/kg/hour by continuous IV
infusion from 8 pm to 6 am beginning the evening after diagnosis of hyperactive or mixed delirium
Participants in both groups were given haloperidol as a rescue medication if required
Outcomes Delirium duration in hours, delirium-free days at 28 days, death (28 days), severity of ICU delirium, number
of ventilator-free days, need for rescue sedation (haloperidol), amount of oral quetiapine, total costs of
medication, length of ICU stay (hours), length of hospital stay (days), depth of sedation (using RASS, or
SAS), depth of sedation in study group (using EEG)
Starting date January 2017.
Contact information alexa.hollinger@usb.ch.
Notes Clinical trials registration: NCT02807467.
EEG: electroencephalogram; ICDSC: Intensive Care Delirium Screening Checklist; ICU: intensive care unit; IV: intravenous; RASS:
Richmond Agitation Sedation Scale; RCT: randomized controlled trial; SAS: Sedation Agitation Scale.
DATA AND ANALYSES
This review has no analyses.
ADDITIONAL TABLES
Table 1. Comparison 1: propofol versus no agent
Outcome: quantity and quality of sleep as measured by PSG, actigraphy, BIS or EEG
Study ID Interventions Measurement tool Narrative results as re- Data; median (IQR)
ported by study authors
Kondili 2012 Cross-over design over 2 PSG No statistically significant Total sleep time (minutes)
nights. difference in sleep time. Propofol: 260 (113-417)
Propofol vs No propofol: 214 (40-285)
no propofol
No statistically significant Total sleep time. Sleep effi-
difference in sleep efficiency (%)
ciency (note: study authors Propofol: 76.3 (28.4-96.9)
do not give a definition of No propofol: 62.6 (13.1-
sleep efficiency) 85.9)
P = 0.37
No statistically significant Total sleep time (%)

difference in Stage 1 sleep. Propofol: 20.8 (5.6-80.6)
No propofol: 30.7 (4.6-66.
7)
P = 1.00

difference in Stage 2 sleep. Propofol: 48.9 (4.8-84.0)
No propofol: 46.1 (3.0-80.
4)
P = 0.66

difference in SWS. Propofol: 0 (0 - 5.8)
No propofol: 0 (0 - 0)
P = 0.75
Statistically less REM sleep Total sleep time (%)

in propofol group. Propofol: 0 (0-0)
No propofol: 1.4 (0-13.0)
P = 0.04
BIS: Bispectral Index; EEG: electroencephalogram; HADS: Hospital Anxiety and Depression Scale; IQR: interquartile range; PSG:
polysomnography; REM: rapid eye movement; SWS: slow wave sleep.
Table 2. Comparison 2: propofol versus propofol at a different rate or dose
Outcome: quantity and quality of sleep as measured through reports of participants or family members or by personnel
assessments
Study ID Interventions Measurement tool Narrative results as re- Data

McLeod 1997 Propofol ANS vs Ramsay Sedation Scale Greater rhythmicity of Median (range) r%
propofol CLS sedation in the interven- ANS: 27 (6-35)
tion group. CLS: 8 (0-56)
Achievement of diurnal ANS: 9/15

rhythm. CLS: 3/14
ANS: additional night sedation; CLS: constant light sedation; r%: percentage fit to a normal 24-hour sleep rhythm (≥ 40% is indicative
of normal 24-hour rhythm); SD: standard deviation.
Table 3. Comparison 3: propofol versus another agent
Outcome: quantity and quality of sleep as measured through reports of participants or family members or by personnel
assessments
Study ID Interventions Measurement tool Narrative results as re- Data

Engelmann 2014 Propofol vs Pittsburgh Sleep Diary Fewer awakenings in the Maximum number of
flunitrazepam propofol group. awakenings per partici-
pant
Propofol: 6
Flunitrazepam: 30
Shorter dura- Maximum duration of

tion of awakenings in the awakenings
propofol group. Propofol: 45 minutes
Flunitrazepam: 390 min-
utes
Total sleep duration sim- Total sleep duration

ilar between groups. Propofol: 6 hours
Flunitrazepam: 5 hours
P = 0.623
Sleep quality significantly Median score for sleep

better in propofol group. quality
Propofol: 2.0
Flunitrazepam: 3.0
P < 0.0001
Table 3. Comparison 3: propofol versus another agent (Continued)
Regeneration and Results not reported by

refreshment significantly authors
better in propofol group
Quality of falling asleep Median score for falling

did not differ between asleep
groups. Propofol: 2.0
Flunitrazepam: 2.0
P = 0.341
Treggiari-Venzi 1996 Propofol vs midazolam HADS Sleep quality improved Mean (± SD) HADS
during 5-day study. No Propofol:
significant differences in day 1: 6.5 (± 3.3)
sleep quality between 2 day 3: 6.6 (± 2.9)
groups* day 5: 7.2 (± 2.3)
(*unclear how HADS Midazolam:
measured this outcome) day 1: 6.3 (± 3.4)
day 3: 6.3 (± 3.2)
day 5: 7.2 (± 2.9)
Outcome: quantity and quality of sleep as measured by PSG, actigraphy, BIS or EEG
Study ID Interventions Measurement tool Narrative results as re- Data as median (IQR)
Engelmann 2014 Propofol vs BIS Significantly lower me- Propofol: 74.05

flunitrazepam dian BIS values in propo- Flunitrazepam: 78.70
fol group. P = 0.016
Flunitrazepam reduced Flunitrazepam at 1st

sedative effect over time. hour: 72.05
Flunitrazepam at 5th
hour: 81.00
Longer time in deep sleep Time in deep sleep

in propofol group. (hours:minutes:seconds)
Propofol: 2:23:30
Flunitrazepam: 1:23:30
Longer time in light Time in light and REM

and REM sleep in fluni- sleep
trazepam group. (hours:minutes:seconds)
Propofol: 1:44:00
Flunitrazepam: 2:34:00
Outcome: anxiety or depression, or both, as measured using validated tools
Table 3. Comparison 3: propofol versus another agent (Continued)
Study ID Interventions Measurement tool Narrative results as re- Data as mean (± SD)
ported by study authors HAD score
Treggiari-Venzi 1996 Propofol vs HADS High levels of anxiety in Propofol:

midazolam both groups. No signifi- day 1: 6.7 (± 3.9)
cant differences in mean day 3: 6.8 (± 3.1)
scores between groups day 5: 5.7 (± 4.1)
Midazolam:
day 1: 6.7 (± 4.7)
day 3: 6.5 (± 4.5)
day 5: 7.5 (± 5.2)
High levels of depres- Propofol:

sion in both groups. day 1: 5.9 (± 4.0)
No significant differences day 3: 6.0 (± 3.0)
in mean scores between day 5: 5.5 (± 3.9)
groups Midazolam:
day 1: 7.5 (± 5.5)
day 3: 6.8 (± 4.8)
day 5: 7.2 (± 5.1)
ANS: additional night sedation; BIS: Bispectral Index; CLS: constant light sedation; EEG: electroencephalogram; HADS: Hospital
Anxiety and Depression Scale; IQR: interquartile range; min: minute; PSG: polysomnography; REM: rapid eye movement; SD:
standard deviation.
APPENDICES
Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Critical Care] explode all trees
#2 MeSH descriptor: [Critical Illness] explode all trees
#3 MeSH descriptor: [Intensive Care Units] explode all trees
#4 MeSH descriptor: [Respiration, Artificial] explode all trees
#5 ((intensive or critical) near/3 (care or unit*)) or (critical* near/3 ill*)
#6 (mechanical* near/3 ventilat*) or (artificial* near/3 respiration*)
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 propofol or sleep*
#9 MeSH descriptor: [Propofol] explode all trees
#10 MeSH descriptor: [Hypnotics and Sedatives] explode all trees
#11 MeSH descriptor: [Sleep] explode all trees
#12 #8 or #9 or #10 or #11
#13 #7 and #12
#14 #13 in Trials
Appendix 2. MEDLINE Ovid search strategy
1. Critical Illness/ or Critical Care/ or exp Intensive Care Units/ or (ICU or ((intensive or critical) adj3 (care or unit*)) or (critical*
adj3 ill*)).mp. or Respiration, Artificial/ or (mechanical* adj3 ventilat*).mp. or (artificial* adj3 respiration*).mp.
2. exp “Hypnotics and Sedatives”/ or Propofol/ or sleep/ or (sleep* or hypnotic* or sedat* or propofol).mp.
3. ((randomized controlled trial or controlled clinical trial).pt. or randomi*.ab. or placebo.ab. or clinical trials as topic.sh. or
randomly.ab. or trial.ti.) not (animals not (humans and animals)).sh.
4. 1 and 2 and 3
Appendix 3. Embase Ovid search strategy

1. critical illness/ or exp intensive care unit/ or exp intensive care/ or (ICU or ((intensive or critical) adj3 (care or unit*)) or
(critical* adj3 ill*)).mp. or artificial ventilation/ or (mechanical* adj3 ventil*).mp. or (artificial* adj3 respiration*).mp.
2. hypnotic sedative agent/ or propofol/ or sleep/ or (sleep* or hypnot* or sedat* or propofol).mp.
3. ((crossover procedure or double blind procedure or single blind procedure).sh. or (crossover* or cross over*).ti,ab. or
placebo*.ti,ab,sh. or (doubl* adj blind*).ti,ab. or (controlled adj3 (study or design or trial)).ti,ab. or allocat*.ti,ab. or trial*.ti,ab. or
randomized controlled trial.sh. or random*.ti,ab.) not ((exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/
or (human or humans).ti.))
4. 1 and 2 and 3
Appendix 4. CINAHL EBSCO search strategy

1. (MM “Critical Illness”)
2. (MM “Critically Ill Patients”)
3. (MH “Critical Care+”)
4. (MH “Intensive Care Units+”)
5. (intensive or critical) N3 (care or unit*) OR critical* N3 ill*
6. (MH “Respiration, Artificial+”)
7. mechanical* N3 ventilat* OR artificial* N3 respiration*
8. (S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7)
9. (MH “Hypnotics and Sedatives+”)
10. (MM “Propofol”)
11. (MH “Sleep+”)
12. sleep* OR hynotic* OR sedat* OR propofol*
13. (S9 OR S10 OR S11 OR S12)
14. TX allocat* random*
15. (MH “Quantitative Studies”)
16. (MH “Placebos”)
17. TX placebo*
18. TX random* allocat*
19. (MH “Random Assignment”)
20. TX randomi* control* trial*
21. TX ((singl* n1 blind*) or (singl* n1 mask*)) or TX ((doubl* n1 blind*) or (doubl* n1 mask*)) or TX ((tripl* n1 blind*) or
(tripl* n1 mask*)) or TX ((trebl* n1 blind*) or (trebl* n1 mask*))
22. TX clinic* n1 trial*
23. PT Clinical trial
24. (MH “Clinical Trials+”)
25. S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24
26. S8 AND S13 AND S25
Appendix 5. PsycINFO EBSCO search strategy
1. MM “Intensive Care”
2. MM “Artificial Respiration”
3. (intensive or critical) N3 (care or unit*) OR critical* N3 ill*
4. mechanical* N3 ventilat* OR artificial* N3 respiration*
5. (S1 OR S2 OR S3 OR S4)
6. MM “Propofol”
7. MM “Sedatives” OR MM “Hypnotic Drugs”
8. DE “Sleep” OR DE “Napping” OR DE “NREM Sleep” OR DE “REM Sleep”
9. sleep* OR hynotic* OR sedat* OR propofol*
10. (S6 OR S7 OR S8 OR S9)
11. DE (“Treatment Effectiveness Evaluation”)
12. DE (“Treatment Outcomes”)
13. DE (“Placebo”)
14. DE (“Followup Studies”)
15. placebo* OR random* OR “comparative stud*” OR clinical N3 trial* OR research N3 design OR evaluat* N3 stud* OR
prospectiv* N3 stud* OR (singl* OR doubl* OR trebl* OR tripl*) N3 (blind* OR mask*)
16. S11 OR S12 OR S13 OR S14 OR S15
17. S5 AND S10 AND S16
Appendix 6. Data extraction form template

Data Collection Form
Study ID
Report IDs of other reports of this study (e.g. duplicate publications, follow-up studies)
1. General Information
Date form completed (dd/mm/yyyy)
Report title
(title of paper/ abstract/ report that data extracted from)
Reference details
Report author contact details
Publication type
(e.g. full report, abstract, letter)
Study funding sources (including role of funders)
(Continued)
Possible conflicts of interest (for study authors)
2. Study Eligibility
Study Characteristics Eligibility criteria Yes No Unclear Location in text

(pg /fig / table)
Type of study Randomized controlled trial

Quasi-randomized controlled trial
Participants Adult >16yrs. Intensive Care Unit

admission
Intervention Propofol
Comparisons No agent; or
A different dose of propofol; or
Another agent, specifically admin-
istered for the promotion of sleep
INCLUDE EXCLUDE
Reason for exclusion
3. Population and setting
Description Location in text

(include comparative information for (pg /fig / table)
each group (i.e. intervention and con-
trols) if available
Population and description

(from which study participants
are drawn)
Inclusion criteria
Exclusion criteria
Method/s of recruitment of
participants
Informed consent obtained Yes/No/Unclear
4. Methods
Descriptions as stated in report/paper Location in text
(pg /fig / table
Aim of study
Design (e.g. parallel, crossover,

cluster)
Unit of allocation
(by individuals, cluster /groups or
body parts)
Ethical approval needed/ob- Yes/No/Unclear

tained for study
Registered with clinical trial Yes/No Clinical trials ID number:

registry
5. Risk of Bias assessment
Domain Risk of bias Support for judgement Location in text

Low/ High/ Unclear (pg /fig / table
Sequence generation
(selection bias)
Allocation concealment
(selection bias)
Baseline Imbalances
Blinding of participants and

personnel
(performance bias)
Blinding of outcome assess-

ment
(detection bias)
Incomplete outcome data

(attrition bias)
Selective outcome reporting

(reporting bias)
Other bias
6. Participants
Description as stated in report/paper Location in text (pg /fig / table
Total no. randomized
Withdrawals and exclusions

(if not provided below by out-
come)
Age Intervention Comparison

age range (mean)
Sex Intervention Comparison

Male/Female
Other baseline characteristics
Post-operative admission or
emergency admission
Co-morbidities
Time in ICU prior to inter-

vention
7.1 Intervention group
Description as stated in report/paper Location in text

(pg /fig / table
Intervention Propofol
No. randomized to group
Description
(dose, method of administration)
Duration of treatment period
Time of administration
Concomitant agents
(type, dose, method of administration etc)
7.2 Comparison groups - repeated as required
(pg /fig / table
Comparison group type

(placebo, no treatment, different drug)
No. randomized to group
Description
(type, dose, method of administration)
Duration of treatment period
Time of administration
Concomitant agents
(type, dose, method of administration etc)
8.1 Outcomes (repeat for each outcome)

(pg /fig / table
Outcome name
Time points measured
Time points reported
Outcome definition
Person measuring/reporting
Unit of measurement
Scales: upper and lower limits

(indicate whether high or low score is good)
Is outcome tool validated? Yes/No/Unclear
Imputation of missing data

(e.g. assumptions made for ITT analysis)
Assumed risk estimate

(e.g. baseline or population risk noted in
Background)
(Continued)
Power
9.1 Results (repeat for each outcome)

(pg & ¶ /fig / table
Comparison
Outcome
Results Intervention Comparison
No. missing partici-

pants and reasons
Any other results re-

ported
Unit of analysis
Statistical meth-
ods used & appropri-
ateness of these meth-
ods
10. Applicability
Have important population groups been Yes No Unclear

excluded from the study?
Does the study directly address the re- Yes No Unclear

view question?
(any issues of partial or indirect applicability)
Are there any limitations in the design of Yes No Unclear

the study?
11. Other information
(pg & ¶ /fig / table
Key conclusion of study authors
References to other relevant studies
Correspondence required for further

study information
(from whom, what and when)
CONTRIBUTIONS OF AUTHORS
Conceiving of the review: SL.
Co-ordinating the review: SL.
Undertaking manual searches: SL, OSR.
Screening search results: SL, OSR.
Organizing retrieval of papers: SL, OSR
Screening retrieved papers against inclusion criteria: SL, OSR.
Appraising the quality of papers: SL, OSR.
Abstracting data from papers: SL, OSR.
Managing data for the review: SL.
Entering data into Review Manager 5: SL.
Analysing Review Manager statistical data: SL, OSR.
Interpreting data: SL.
Writing the review: SL.
Securing funding for the review: AS.
Serving as guarantor for the review: AS.
Taking responsibility for reading and checking the review before submission: SL, OSR, PA, AS.
DECLARATIONS OF INTEREST
SL: see Sources of support.
OSR: see Sources of support.
PA’s institution receives a National Institute for Health Research (NIHR) Cochrane Collaboration Programme Grant for programme
of reviews in perioperative care, which supported his work on this review; see Sources of support. Dr Alderson is employed by the
National Institute for Heath and Care excellence (NICE).
AS’s institution receives the NIHR Cochrane Collaboration Programme Grant for programme of reviews in perioperative care (see
Sources of support).
SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• NIHR Cochrane Programme Grant: 13/89/16, UK.
This project was supported by the National Institute for Health Research (NIHR), via Cochrane Programme Grant funding. The
views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the Systematic Reviews
Programme, NIHR, UK National Health Service (NHS) or the Department of Health.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We made the following changed to the published protocol (Lewis 2016).
1. Title: we edited our title to reflect that the review population was adults.
2. Objectives: we clarified the objective to state ’adults rather than ’patients’ to reflect the review’s intention to assess sleep in only
adults.
3. Methods: we edited the type of participants to improve clarity. We added the inclusion of patients with trauma.
4. Data extraction and management: we did not use Covidence to record data extraction decisions. We edited the review to reflect
use of a standard data extraction form.

Propofol For The Promotion of Sleep in Adults in The Intensive Care Unit (Review)

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Propofol For The Promotion of Sleep in Adults in The Intensive Care Unit (Review)

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Cochrane Database of Systematic Reviews

Propofol for the promotion of sleep in adults in the intensive

Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF

Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF.

Propofol for the promotion of sleep in adults in the intensive

Sharon R Lewis1 , Oliver J Schofield-Robinson2 , Phil Alderson3 , Andrew F Smith4

Editorial group: Cochrane Anaesthesia, Critical and Emergency Care Group.

PLAIN LANGUAGE SUMMARY

Patient or population: critically ill adults in the intensive care unit

Outcomes Impacts No of Participants Quality of the evidence Comments

Quantity and quality of sleep as Not reported. - - -

Anxiety or depression, or both, as Not reported. - - -

Adverse events (such as car- Not reported. - - -

GRADE Working Group grades of evidence

Why it is important to do this review

We noted a large number of losses in Engelmann 2014, and tech-

Comparison 2: propofol versus propofol at a different

2. Adverse events (such as cardiovascular events, respiratory

Patient or population: critically ill adults in the intensive care unit

Outcomes Impacts No of Participants Quality of the evidence Comments

Quantity and quality of sleep as Not reported. - - -

Anxiety or depression, or both, as Not reported. - - -

Adverse events (such as car- Not reported. - -

BIS: Bispectral Index; EEG: electroencephalogram ; PSG: polysom nography.

GRADE Working Group grades of evidence

Patient or population: critically ill adults in the intensive care unit

Outcomes Impacts No of Participants Quality of the evidence Comments

Adverse events (such as car- Not reported. - - -

BIS: Bispectral Index; EEG: electroencephalogram ; PSG: polysom nography.

GRADE Working Group grades of evidence

Implications for practice ACKNOWLEDGEMENTS

Characteristics of included studies [ordered by study ID]

Participants Total number of randomized participants: 66.

Interventions Propofol group:

Notes Funding/declarations of interest: departmental funding.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No details.

Participants Total number of randomized participants: 13.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No details.

Participants Total number of randomized participants: 30.

Notes Funding/declarations of interest: sponsored by Zeneca Pharmaceuticals

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No details.

Participants Total number of randomized participants: 40.

Interventions Propofol group:

Outcomes Levels of anxiety and depression.

Notes Funding/declarations of interest: no details.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No details.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

ICU: intensive care unit; RCT: randomized controlled trial.

Participants Mechanically ventilated patients in the ICU.

Interventions Circadian rhythm vs daily interruption vs continuous sedation or demand sedation

Outcomes Recovering natural circadian rhythm, duration of mechanical ventilation

Interventions Dexmedetomidine vs GABA agonist (e.g. propofol, benzodiazepines)

Characteristics of ongoing studies [ordered by study ID]

Participants Target number of randomized participants: 316.

Interventions Propofol group:

Starting date January 2017.

Contact information alexa.hollinger@usb.ch.

Notes Clinical trials registration: NCT02807467.