Journal of Clinical Anesthesia 59 (2020) 74–81

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Journal of Clinical Anesthesia

journal homepage: www.elsevier.com/locate/jclinane

Original Contribution

The effect of melatonin on delirium in hospitalised patients: A systematic T

review and meta-analyses with trial sequential analysis
⁎
Ka Ting Ng (Medical Officer (Doctor))a, , Wan Yi Teoh (Medical student)b, Ai Jing Khor (Medical
student)c
a
Department of Anaesthesiology, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Malaysia
b
University of Liverpool, School of Medicine, Cedar House, Ashton Street, Liverpool L69 3GE, United Kingdom
c
International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

A R T I C LE I N FO A B S T R A C T S

Keywords: Objectives: Melatonin is an endogenous hormone, which regulates circadian rhythms and promotes sleep. In
Agitation recent years, several randomised controlled trials examining the prophylactic use of melatonin to prevent de-
Delirium lirium were published with conflicting findings. The primary aim of this review was to determine the effect of
Length of hospital stay melatonin on the incidence of delirium in hospitalised patients.
Melatonin
Data sources: MEDLINE, EMBASE and CENTRAL were systematically searched from their inception until
Ramelteon
December 2018.
Review methods: All randomised clinical trials were included.
Results: Sixteen trials (1634 patients) were included in this meta-analysis. Incidence of delirium was not sig-
nificantly lower in patients who received melatonin, with an odd ratio, OR (95%Cl) of 0.55 (0.24–1.26);
ρ = 0.16, certainty of evidence = low, trial sequential analysis = inconclusive. However, patients who rando-
mised to melatonin had a significantly shorter length of stay in intensive care units, with a mean difference, MD
(95%CI) of −1.84 days (−2.46, −1.21); ρ < 0.001. No differences were demonstrated in the need for physical
restraints (OR 95%Cl 0.65; 0.31–1.37; ρ = 0.26) and the requirement of sedative agents (OR 95%Cl 0.86;
0.48–1.55; ρ = 0.62).
Conclusions: In summary, the results of this meta-analysis of sixteen trials neither support nor oppose the use of
melatonin in the prevention of delirium of hospitalised patients. We identified high heterogeneity across all the
included trials and low certainty of evidence with potential type II error. Future multi-centre, adequately
powered randomised controlled trials are warranted to provide more certainty on the use of melatonin for the
prevention of delirium.
PROSPERO: CRD42019123546.

1. Introduction
The incidence of delirium is highly prevalent amongst hospitalised
in-patients, ranging from 18% in general wards to as high as 83.3% in
intensive care units (ICU) [1,2]. This is a common neuropsychiatric
syndrome, which contributes to significant morbidity and mortality [3].
It is seen in particularly vulnerable elderly patients with cognitive im-
pairment, resulting in a longer hospital stay and a long-term decline in
functional outcomes [4–6]. However, the causes of delirium are mul-
tifactorial, including infections, drugs, general anaesthesia, surgery and
sleep deprivation [1,3,5–7].
Melatonin is an endogenous pleiotropic hormone produced by
pineal gland, which responds to night darkness in order to promote the
onset of sleep and regulate the sleep-wake cycle [8]. It is believed to
have anti-oxidant and anti-inflammatory effects in human and animal
studies, which may target the inflammatory pathway of delirium
[9–14]. The potential roles of melatonin as an anti-nociceptive, anxio-
lytic and sedative agents were shown in several studies [15–19]. Ob-
servational studies have demonstrated that low levels of serum mela-
tonin was associated with a higher occurrence of delirium after surgery
or sleep deprivation in the ICU patients, in comparison to those without
delirium [20–22]. Hatta and colleagues demonstrated the protective
effect of melatonin agonist, ramelteon amongst elderly patients with
dementia, where the effect was more prominent amongst those

⁎
Corresponding author.
E-mail address: katingng1@gmail.com (K.T. Ng).

https://doi.org/10.1016/j.jclinane.2019.06.027
Received 14 May 2019; Received in revised form 11 June 2019; Accepted 24 June 2019
0952-8180/ © 2019 Elsevier Inc. All rights reserved.
K.T. Ng, et al.
admitted to ICUs [23]. Several long term studies in children and adults
receiving oral melatonin did not document any significant adverse ef-
fects of melatonin [24–28]. Thus, melatonin could be a cost-effective
preventive measure to prevent delirium if restoring normal level of
melatonin is associated with a reduced incidence of delirium amongst
hospitalised patients. Reviews by Aghakouchakzadeh and Chakraborti
have supported the promising effect of melatonin for the prevention of
delirium amongst elderly patients and critically-ill patients [29,30]. In
recent years, several randomised controlled trials have examined the
protective role that melatonin plays in the prevention of delirium in
hospitalised patients with contrary findings [31–35]. The efficacy and
safety profile of melatonin and melatonin agonist remains uncertain in
the literature. Whilst the roles of that melatonin plays in the prevention
of delirium are desirable, a systematic review and meta-analysis is
warranted before recommendations on the use of melatonin in hospi-
talised patients can be made.
We hypothesised that the supplementation of exogenous melatonin
reduced the incidence of delirium in hospitalised patients by synchro-
nising the internal circadian rhythms and the sleep-wake cycle. The
primary aim of this systematic review was to examine the prophylactic
use of melatonin and melatonin agonist in the prevention of delirium in
hospital. Secondary aims were to determine the effects of melatonin
and melatonin agonist on the need for physical restraints or sedative
agents, all-cause and ICU mortality, length of stay in ICU and hospital,
duration of ventilation and common adverse events of melatonin
(nausea, dizziness, headache and paraesthesia).
2. Methods
This review was conducted and reported in accordance with the
Cochrane Handbook for Systematic Reviews of Interventions [36]. The
review protocol was published on PROSPERO (CRD42019123546)
prior to the commencement of literature search. The research questions
were formulated using a population-intervention-comparison-outcomes
(PICO) approach (eTable 1, Online Digital Supplement).
2.1. Search strategy
Databases of EMBASE, Medline and CENTRAL were systematically
searched from its inceptions until December 2018 for parallel-arm
randomised controlled trials (RCTs) comparing melatonin/ melatonin
agonist (ramelteon) and placebo in hospitalised patients. The
ClinicalTrials.gov and the WHO International Clinical Trials Registry
Platform Search Portal were searched for any ongoing or unpublished
trials. No restrictions were applied on language and date of publication.
The search term and strategy are outlined in eTable 2. Inclusion cri-
teria:
1. RCTs
2. Examining the prophylactic use of melatonin/ melatonin agonist
versus placebo in the prevention of delirium
3. Hospitalised adult patients (≥18 years old).
Observational studies, case series, case reports and trials published
as abstracts were excluded. Trials examining the combination of mel-
atonin with other confounders (ear plugs, eye mask and light) were
excluded. Trials with healthy volunteers were also excluded in this
review. The references of all included papers and relevant systematic
reviews were hand-searched for additional studies.
2.2. Outcomes
The primary outcome of this review was the incidence of delirium.
All available data on the follow-up duration was recorded. For data
analysis purposes, the longest reported follow-up for each study was
used. Secondary outcomes were the need for physical restraints, need
75
Journal of Clinical Anesthesia 59 (2020) 74–81
for sedative agents, all-cause and ICU mortality, length of stay in ICU
and hospital, duration of ventilation and common reported adverse
events of melatonin (nausea, dizziness, headache, paraesthesia).
2.3. Study selection and data extraction
Two authors (WT, AK) independently screened the title and ab-
stracts. Any discrepancy was resolved via a discussion with a third
author (KN). Both authors (WT and AK) independently screened the full
texts and any conflict was resolved by a third author (KN). Selection of
final included studies was based on the final consensus amongst all the
three authors (KN, WT, AK). Data from the included studies were ex-
tracted using a standardised data extraction form. Both authors (WT,
AK) independently used the Cochrane Risk of Bias Assessment tool to
assess the risk of bias for all the included RCTs. Any disagreements were
resolved via a discussion with a third author (KN).
2.4. Statistical analysis
The Review Manager version 5.3 was used for statistical analyses. A
two-tail ρ-value < 0.05 was considered as statistical significance in all
the reported outcomes. Findings were reported as odd ratio (OR) and
mean difference (MD) for binary and continuous outcomes, respec-
tively. Due to variation of study population, clinical settings and dosage
of melatonin agonist, I-square (I2) test was used to assess the hetero-
geneity of studies. The I2 value of < 40%, 40%–60%, > 60% were ca-
tegorised as low, moderate and substantial, respectively. A fixed-effect
model (Mantel–Haenszel method) was used to pool estimates. If
I2 > 60% was observed, a random-effect model (DerSimonian–Laird
method) was used. Various delirium assessment tools (Abbreviated
Mental Test- AMT, Confusion Assessment Method- CAM, Diagnostic and
Statistical Manual of Mental Disorders-DSM IV) were utilised across
different trials. Subgroup analyses of primary outcome were planned by
stratifying them into different assessment tools, different clinical set-
tings (ICU and hospital ward) and different types of melatonin (mela-
tonin vs ramelteon). To ensure the robustness of our primary outcome,
sensitivity analysis was performed based on studies with low risk of
bias.
The GRADE assessment of evidence and summary of findings were
independently performed by two authors (WT, AK). The certainty of
evidence was assessed based on the five criteria (risk of bias, incon-
sistency, indirectness, imprecision and publication bias). Any dis-
crepancy was resolved by a third author (KN). Trial sequential analysis
was performed on the primary outcome to prevent the risk of random
error and multiplicity phenomenon as a result of repeated significance
testing across all the included trials. The required information size was
calculated based on a two-sided sequential analysis fixed-effect model
with 5% risk of type 1 error, 80% of power, relative risk reduction of
20% and 28.09% of incidence of control arm.
3. Results
The flow of studies is shown in the Fig. 1. After screening titles/
abstracts of 861 citations, thirty-one articles were retrieved for full
texting screening. Of these, sixteen articles were included in this ana-
lysis. Searching of clinical trial registers identified 13 ongoing trials
(eTable 3). Details of excluded studies are outlined in the eTable 4.
3.1. Study characteristics
The clinical characteristics of included studies are illustrated in
Table 1. Of the 16 included RCTs, the majority were single-centred and
three [23,34,37] were of multi-centred. All the RCTs administered
melatonin via enteral route. Of all, two RCTs [23,31] administered
melatonin agonist, ramelteon which has stronger affinity to MT1 and
MT2 receptor than melatonin [38]. The dosage of melatonin ranged
K.T. Ng, et al.
Fig. 1. PRISMA flow diagram.
from 0.5 mg to as high as 50 mg/kg. The regime of melatonin varied
across all the included trials. Seven trials [31,32,35,39–42] were con-
ducted in ICUs, eight studies [33,34,37,43–47] were in hospital wards
and another one [23] included patients from both ICUs and hospital
wards. The average mean of age for all the included RCTs was > 50
years old. In the overall risk of bias assessment, twelve trials were of
low risk and four [23,43,44,46] were of unclear/high risk (eTable 5).
The summary of findings and PRISMA checklist were tabulated in
Table 2 and eTable 6, respectively.
3.2. Primary outcome
All the primary and secondary outcomes, the number of included
RCTs, number of patients, OR/ MD, I2, and ρ-value are outlined in
Table 3. The incidence of delirium for the melatonin group was 19.8%
and 26% in the placebo group, where the difference was not statistically
significant (OR 0.55, 95% CI 0.24 to 1.26; participants = 1047; stu-
dies = 9; certainty of the evidence: moderate). The statistical hetero-
geneity was substantial (I2 = 76%) where different delirium assessment
tools were used across all the included trials with different degree of
sensitivity and specificity. In the subgroup analyses, there was no sig-
nificant differences amongst different types of delirium assessment
tools, clinical settings and types of melatonin. Sensitivity analysis of
RCTs with low risk of bias demonstrated no changes in the magnitude
and direction of estimate effect of delirium.
In the trial sequential analysis, the required information size for
delirium is 18,337 patients, based on 5% of type 1 error (two-sided), a
power of 80% and 28.09% of incidence of control arm. At this stage of
review, with 1047 patients, only 5.7% of the required information size
was available to detect statistical significance of melatonin for the re-
lative risk reduction of 20% (Fig. 2). Although the cumulative z-curve
(blue line) crossed the trial sequential analysis monitoring for benefits
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Journal of Clinical Anesthesia 59 (2020) 74–81
(red line), it is still inconclusive that melatonin affects the incidence of
delirium as it did not surpass the required information size.
3.3. Secondary outcomes
In comparison to the placebo group, the need for physical restraints
(OR 0.65, 95% CI 0.31 to 1.37; participants = 204; studies = 2; cer-
tainty of the evidence: high) and sedative agents (OR 0.86, 95% CI 0.48
to 1.55; participants = 216; studies = 3; certainty of the evidence:
moderate) were not significantly reduced in those patients who were
randomised to melatonin. Patients who received melatonin had a sig-
nificantly shorter ICU stays (MD −1.84 days, 95% CI -2.46 to −1.21;
participants = 411; studies = 5; certainty of the evidence: high) than
the placebo group. The duration of mechanical ventilation (MD
−1.69 days, 95% CI -3.92 to 0.53; participants = 138; studies = 2) and
hospital length of stay (MD −1.01 days, 95% CI -2.80 to 0.79; parti-
cipants = 634; studies = 6; certainty of the evidence: moderate) were
not significantly lowered in the melatonin group. Neither benefits nor
harms of melatonin were demonstrated in term of all-cause mortality
(OR 0.92, 95% CI 0.62 to 1.38; participants = 582; studies = 3; cer-
tainty of the evidence: high), ICU mortality (OR 0.91, 95% CI 0.48 to
1.73; participants = 363; studies = 4; certainty of the evidence: high),
nausea (OR 1.35, 95% CI 0.71 to 2.57; participants = 355; studies = 5),
dizziness (OR 1.42, 95% CI 0.73 to 2.74; participants = 307; stu-
dies = 4), headache (OR 0.99, 95% CI 0.42 to 2.34; participants = 207;
studies = 3) and paraesthesia (OR 1.59, 95% CI 0.60 to 4.20; partici-
pants = 183; studies = 2).
4. Discussions
Our meta-analysis demonstrated that the use of melatonin and ra-
melteon do not reduce the incidence of delirium in hospitalised
 K.T. Ng, et al.

Table 1
Clinical characteristics of included studies.
Author Year Study design Route Comparator Dosage (mg) Timing Control Setting Condition Age Sample size Country Overall risk
(mean ± SD) of bias

Asayama 2003 Single centre Enteral Melatonin 3 mg 2030H for 4 weeks Placebo Hospital ward Alzheimer's disease in a M: 78.9 ± 7.3 20 Tokyo Unclear
RCT geriatric ward P: 79.4 ± 5.3
Ibrahim 2006 Single centre Enteral Melatonin 3 mg 2200H for 48 h Placebo ICU Mixed medical-surgical ICU M: 63 ± 15.6 32 Australia Low
RCT P: 57 ± 22.1
Bourne 2008 Single centre Enteral Melatonin 10 mg 2100H for four nights Placebo ICU Mixed medical-surgical ICU M: 69.9 ± 12.0 25 UK Low
RCT P: 58.7 ± 12.5
Sultan 2010 Single centre Enteral Melatonin 5 mg At sleep time and 90 min before Placebo Hospital ward Hip arthroplasty surgery M: 70.4 ± 7.1 102 Saudi Arabia Unclear
RCT operation P: 72.3 ± 6.4
Al-aama 2011 Single centre Enteral Melatonin 0.5 mg Daily between 1800 and 2400H for Placebo Hospital ward Internal medicine ward, M: 84.3 ± 5.9 145 Canada Low
RCT 14 days regardless of any diseases P: 84.6 ± 6.2
Nickkhologh 2011 Single centre Enteral Melatonin 50 mg/kg After intubation for GA on the day Placebo ICU Liver resection surgery M: 59 ± 10 50 Germany Low
RCT of surgery P: 56 ± 11
Dejonghe 2014 Multicentre Enteral Melatonin 3 mg 2100H for 5 days Placebo Hospital ward Hip fracture surgery M: 84.1 ± 8.0 452 Netherlands Low
RCT P: 83.4 ± 7.5
Hatta 2014 Multicentre Enteral Ramelteon 8 mg 2100H for 7 days Placebo Mixed ICU and Mixed medical-surgical ICU M: 78.2 ± 6.6 67 Japan High

77
RCT hospital ward and regular acute wards P: 78.3 ± 6.8
Hansen 2014 Single centre Enteral Melatonin 6 mg 1 h before bedtime 1-week Placebo Hospital ward lumpectomy/mastectomy M: 54.3 ± 15.6 54 Denmark Low
RCT preoperatively and 12 weeks post- surgery P: 59 ± 14.9
operative
Kirskey 2015 Single centre Enteral Melatonin 5 mg 72 h before operation and continue Placebo Hospital ward Total knee arthroplasty M: 70 ± 9.3 50 United State High
RCT 72 h postoperatively surgery P: 61.4 ± 14.3
Mistraletti 2015 Single centre Enteral Melatonin 3 mg 2000H from third ICU day till Placebo ICU Mixed medical-surgical ICU M: 68 ± 15 82 Italy Low
RCT discharge P: 65 ± 15
Vijayakumar 2016 Single centre Enteral Melatonin 3 mg 2100H throughout ICU stay Placebo ICU Organophosphate poisoning M: 36.9 ± 10.3 56 India Low
RCT patients in ICU P: 38 ± 14.4
Fan 2017 Multicentre Enteral Melatonin 1 mg 1 h before bedtime 1 day before Placebo Hospital ward Hip arthroplasty surgery M: 74.5 ± 5.7 148 China Low
RCT surgery, 5 consecutive days P: 74.6 ± 5.4
postoperatively
Jaiswal 2018 Single centre Enteral Melatonin 3 mg 2100H for 14 days Placebo Hospital ward Internal medicine ward, M: 81.2 ± 7.3 87 United State Low
RCT regardless of any diseases P: 80.1 ± 8.3
Abbasi 2018 Single centre Enteral Melatonin 3 mg 24 h after admission for 5 Placebo ICU medical, surgical and trauma M: 52.5 ± 18.4 172 Iran Low
RCT consecutive days ICU P: 49.9 ± 19.0
Nishikimi 2018 Single centre Enteral Ramelteon 8 mg at 2000H every day until discharge Placebo ICU emergency ICU, medical ICU M: 66.7 ± 13.8 92 Japan Low
RCT from ICU P: 66 ± 19.9

RCT- randomised controlled trial, ICU- intensive care unit; H– hour, M- melatonin; P- placebo; GA- general anaesthesia.
Journal of Clinical Anesthesia 59 (2020) 74–81
K.T. Ng, et al. Journal of Clinical Anesthesia 59 (2020) 74–81

Table 2
Summary of findings.
Outcomes Anticipated absolute effects⁎ (95% CI) Relative effect № of participants Certainty of the evidence
(95% CI) (studies) (GRADE)
Risk with Risk with Melatonin
placebo

Incidence of delirium 260 per 1000 162 per 1000 (78 to 307) OR 0.55 (0.24 to 1047 (9 RCTs)
1.26)
Length of intensive care – The mean length of intensive care unit stay in the – 411 (5 RCTs)
unit stay intervention group was 1.84 lower (2.46 lower to 1.21
lower)
Length of hospital stay – The mean length of hospital stay in the intervention – 634 (6 RCTs)
group was 1.01 lower (2.8 lower to 0.79 higher)
Need for physical restraint 225 per 1000 159 per 1000 (83 to 285) OR 0.65 (0.31 to 204 (2 RCTs)
1.37)
Need for sedative agents 450 per 1000 413 per 1000 (282 to 559) OR 0.86 (0.48 to 216 (3 RCTs)
1.55)
Intensive care unit 130 per 1000 120 per 1000 (67 to 206) OR 0.91 (0.48 to 363 (4 RCTs)
mortality 1.73)
All-cause mortality 218 per 1000 204 per 1000 (147 to 277) OR 0.92 (0.62 to 582 (3 RCTs)
1.38)

GRADE Working Group grades of evidence

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that
it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Explanations.
a. Wide variation of estimate effect and substantial heterogeneity.
b. Total number of events < 300.
c. Funnel plot suggestive of publication bias.
⁎
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the
intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio; MD: Mean difference.

Table 3
Data analysis of primary and secondary outcomes.
Outcomes Trials n I2 (%) MD/OR (95% CI) ρ

1 Delirium 9 1047 76 0.55 (0.24 to 1.26) 0.16

1.1 Delirium – subgroup analysis by delirium assessment tools
CAM 5 476 71 0.56 (0.18 to 1.73) 0.32
DSM-4 2 445 86 0.34 (0.02 to 6.24) 0.47
AMT 1 102 – 0.21 (0.07 to 0.64) 0.006
Unknown 1 24 – 0.50 (0.18 to 1.39) 0.16
Test for subgroup differences: Chi2 = 5.94, df = 3 (P = 0.11), I2 = 49.5%
1.2 Delirium- subgroup analysis by clinical settings
ICUs 4 305 67 0.74 (0.19 to 2.82) 0.66
Hospital wards 4 675 81 0.62 (0.19 to 2.01) 0.43
Combination of hospital wards and ICUs 1 67 – 0.07 (0.01 to 0.54) 0.01
Test for subgroup differences: Chi2 = 3.58, df = 2 (P = 0.17), I2 = 44.2%
1.3 Delirium- subgroup analysis by types of melatonin
Melatonin 7 892 76 0.74 (0.29 to 1.92) 0.54
Ramelteon 2 155 56 0.20 (0.04 to 1.07) 0.06
Test for subgroup differences: Chi2 = 1.77, df = 1 (P = 0.18), I2 = 43.4%
1.3 Delirium- Sensitivity analysis (studies at low risk of bias) 7 878 73 0.79 (0.33 to 1.88) 0.60
2 Needs for physical restraints 2 204 0 0.65 (0.31 to 1.37) 0.26
3 Needs for sedative agents 3 216 4 0.86 (0.48 to 1.55) 0.62
4 Duration of mechanical ventilation (days) 2 138 0 −1.69 (−3.92 to 0.53) 0.14
5 Length of ICU stay (days) 5 411 49 −1.84 (−2.46 to −1.21) < 0.001
6 Length of hospital stay (days) 6 634 86 −1.01 (−2.80 to 0.79) 0.27
7 All-cause mortality 3 582 0 0.92 (0.62 to 1.38) 0.70
8 ICU mortality 4 363 0 0.91 (0.48 to 1.73) 0.77
9 Nausea 5 355 0 1.35 (0.71 to 2.57) 0.35
10 Dizziness 4 307 0 1.42 (0.73 to 2.74) 0.30
11 Headache 3 207 26 0.99 (0.42 to 2.34) 0.98
12 Paraesthesia 2 183 0 1.59 (0.60 to 4.20) 0.35

AMT- Abbreviated Mental Test, CAM- Confusion Assessment Method, DSM-IV- Diagnostic and Statistical Manual of Mental Disorders-IV, ICUs- Intensive Care Units.

78
K.T. Ng, et al.
patients. However, patients who received melatonin and ramelteon had
a significant shorter duration of ICU stay, but not hospital stay or
duration of mechanical ventilation. There were no clear benefits of
melatonin on the need of physical restraints or use of sedative agents.
No significant differences were noted on all-cause mortality, ICU mor-
tality and common adverse effects of melatonin (nausea, dizziness,
headache, paraesthesia). The general quality of evidence ranged from
moderate to high, due to inconsistency, imprecision, dose-response ef-
fect and publication bias in some of the reported outcomes.
To the best of our knowledge, this is the most comprehensive review
summarising the clinical use of melatonin and ramelteon for the pre-
vention of delirium in hospitalised patients. An exhaustive literature
search was conducted and all the included RCTs underwent a rigorous
methodological and quality of evidence assessment. Chakraborti and
team performed a systematic review comparing melatonin and mela-
tonin agonist with placebo for the prevention of delirium in elderly
[29]. Their review identified sparse data and the authors did not con-
duct meta-analysis on the incidence of delirium [29]. It suggested that
melatonin and ramelteon could be safely prescribed to elderly who are
at high risk of delirium based on three included RCTs [23,44,45]. In a
meta-analysis of 4 RCTs, Chen and colleagues concluded that exo-
genous melatonin supplementation had a significant preventive effect
in delirium in elderly patients who admitted to medical wards [48].
However, the search of the previous meta-analysis was until April 2015
with language restriction [48]. In this meta-analysis, we updated the
search until December 2018 by including an additional 12 RCTs
[31–35,39–43,46,47]. A scoping study [49] by Choy and team had in-
cluded 5 RCTs, 3 observational studies and 1 case report. This study had
missed out two RCTs [35,40] examining the effect of melatonin for the
prevention of delirium in hospitalised patients. The inclusion of ob-
servational studies and non-systematic search introduced significant
bias to their findings [49].
The incidence of delirium in our review was 26% in the placebo
group and 19.8% in the melatonin group, the difference being not
statistically significant. Our finding was similar to a Cochrane review of
3 low-quality RCTs, which reported no role of melatonin for the pre-
vention of delirium in hospitalised non-ICU patients [50]. In this
79
Journal of Clinical Anesthesia 59 (2020) 74–81
Fig. 2. Trial sequential analysis of in-
cidence of delirium
X-axis: the number of patients randomised;
Y-axis: the cumulative Z-score; The blue
cumulative z-curve was constructed using a
fixed-effects model (Odds Ratio). The green
cumulative z-curve was constructed using
the law of the iterated logarithm with 5%
risk of type 1 error (two-sided), λ = 2. Red
vertical line with diamonds: required in-
formation size of a meta-analysis. (For in-
terpretation of the references to colour in
this figure legend, the reader is referred to
the web version of this article.)
review, we showed no significant differences in the incidence of de-
lirium for both population of hospital wards and ICUs. However, this
finding conflicted with a review [49], which suggested the potential
role of melatonin in reducing the incidence of delirium. The finding of
this review needs to be interpreted with caveat as it was a non-sys-
tematic review [49]. At present, the trial sequential analysis was in-
conclusive, which this review achieved only 5.7% of required in-
formation size in order to detect significance difference of melatonin
with a relative risk reduction of 20% in the incidence of delirium.
Substantial degree of heterogeneity was noted, which could be attrib-
uted by variation of delirium assessment tools, inadequate sample size,
different dosages, duration and regime of melatonin administered
across all the included trials. The primary outcome of the majority
studies was the incidence of delirium, which minimised reporting bias
in this meta-analysis.
Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) and
International Classification of Diseases, 10th Revision (ICD-10) remain
the standard diagnostic criteria for delirium [38]. Different delirium
screening tools were used to diagnose delirium across all the included
trials. Sultan and team utilised a non-validated tool, Abbreviated
Mental Test to diagnose delirium, which was initially designed to detect
cognitive impairment [44]. Three studies [33,35,45] used CAM test and
two studies [31,32] utilised CAM-ICU test. The specificity and sensi-
tivity of CAM test varied when it was used in different clinical settings,
namely ICU [35] and hospital ward [33,45]. CAM-ICU test was in-
troduced to assess non-verbal patients for delirium in ICU setting based
on CAM algorithm [51]. It is believed to have wider predicting range
than CAM test with almost similar degree of sensitivity and specificity
for delirium [38]. Standardising the delirium screening tool in future
studies could eliminate the risk of measurement bias for the incidence
of delirium.
In this review, we reported that melatonin significantly reduced the
length of stay in ICU, but had no effect on the duration of ventilation,
length of hospital stay, need for physical restraints and sedative agents.
These results need to be interpreted with cautions as all the afore-
mentioned confounders were not adjusted at this review level. In
Vijayakumar's study, critically ill patients who were randomised to
K.T. Ng, et al.
3 mg of melatonin throughout the ICU stay depicted a significant de-
crease in the incidence of delirium [35]. However, the preventive effect
of melatonin did not translate into the duration of ICU stay. In contrast,
with the same dosage of melatonin, two recent RCTs [31,32] of small
sample size revealed the potential benefits of melatonin in reducing
both the occurrence rate of delirium and decreasing the length of ICU
stay. The use of concomitant medications varied across studies, which
introduce variances to the length of ICU/ hospital stay and the need for
physical restraints/ sedative agents. Certain drugs such as benzodia-
zepine and opioids may increase the risk of delirium [52]. Different
nature and clinical characteristics of medical and surgical ICU patients
may affect the length of ICU/hospital stay.
Melatonin is a lipid soluble hormone, which has a short half-life of
45 min with bioavailability ranging from 10 to 56% [53]. Wide of range
of bioavailability may be due to impurity and variation of effective
concentration of medications by manufacturers [54]. It undergoes an
extensive hepatic first pass metabolism [53]. The onset and peak con-
centration are within 50 min and 2.5 h, respectively [53–55]. In our
review, the dosage of melatonin varied significantly across all the in-
cluded trials, ranging from 0.5 mg to 50 mg/kg. No significant differ-
ences were demonstrated in all-cause mortality, ICU mortality and
common adverse effects of melatonin. A meta-analysis of 17 RCTs
showed no evidence of adverse effects of melatonin with short term use
(three months or less) [56]. As melatonin is marketed as a dietary
supplement [54], further studies are required to examine the long-term
safety and efficacy of melatonin in clinical practice. Melatonin is be-
lieved to upregulate antioxidant enzymes and scavenge free radicals to
limit damage to the brain tissues [8]. It is believed that pro-in-
flammatory mediators such as cytokines and prostaglandins contribute
to neuroinflammation, leading to cognitive dysfunction including de-
lirium. Nickkhologh and colleagues utilised a single high dose mela-
tonin (50 mg/kg) to investigate the properties of antioxidant and anti-
inflammatory in patients underwent liver resection [42]. However,
several studies revealed that high dose of melatonin (> 2 mg) may at-
tribute to the next-day carryover effect by producing supra-physiolo-
gical level of melatonin, resulting in daytime sleepiness [57–60]. There
are some discrepancies amongst pharmacokinetics studies in identifying
the optimal dose of melatonin in different population [8]. Mistraleti
and Demuro reported that critically ill patients who received 3 mg of
melatonin achieved peak plasma concentrations 10 times faster than
healthy cohort with a slower plasma clearance [61,62]. The majority of
our included trials used melatonin > 2 mg and no phenomenon of
supra-physiological melatonin was observed in this review. The dura-
tion of melatonin given in each trial differed, ranging from one day to
48 days. It could be a determinant factor to manifest the anti-in-
flammatory and antioxidant effect of melatonin on the pathway of
delirium secondary to infection, general anaesthesia, medications and
surgical stress [19]. Future pharmacokinetics and pharmacodynamics
studies of melatonin are warranted to investigate the optimal dose and
time-response relationship of melatonin in order to achieve steady-state
concentration for its therapeutic effect in different population. The
dosage and duration of melatonin should be standardised in future
trials to minimise the degree of heterogeneity and dose-response gra-
dient in our measured outcomes.
Melatonin acts on MT1, MT2 and MT3 receptors of pituitary gland,
suprachiamatic nucleus of hypothalamus, retina and brain tissues [53].
Ramelteon is a selective melatonin agonist, which has higher affinity to
MT1 and MT2 with longer half-life than melatonin [53]. Ramelteon
does not bind to MT3, serotonin and BDZ receptors in brain, which are
believed to be part of the pathway for delirium [53]. There were only
two RCTs [23,31] with small sample size using ramelteon 8 mg, which
demonstrated positive benefits of melatonin for the prevention of
melatonin in hospitalised ICU patients. Currently, five ongoing RCTs
(NCT02324153; NCT02564939; NCT02691013; UMIN000028436;
NCT03165695) were identified, which will provide robust evidence of
ramelteon use for the prevention of delirium.
80
Journal of Clinical Anesthesia 59 (2020) 74–81
One of the main limitations in this meta-analysis was the lack of
uniformity of the diagnostic criteria for delirium with varied dosage
and duration of melatonin in the included trials. Other limitations were
common to other meta-analysis, such as differences in patients' baseline
characteristics, use of concomitant medications and different clinical
settings. None of the included studies were adequately powered for
sample size and future studies are warranted to determine the pre-
ventive effect of melatonin on delirium in hospitalised patients. The
exclusion of trials published as abstract or presented at conference
could potentially introduce publication bias to our findings.
In this meta-analysis of sixteen RCTs, a high degree of heterogeneity
and inconclusive trial sequential analysis limits us from drawing any
firm recommendations on the use of melatonin for the prevention of
delirium in clinical practice. However, melatonin use was associated
with shorter length of ICU stays and was well-tolerated in all the in-
cluded studies.
Conflict of interest and source of funding
All authors have declared that they do not have any conflicts of
interest in this review. No funding was received in support of this
project.
Authors' contributions
KN: Protocol/ project management, Data collection or management,
Data analysis, Manuscript writing/editing.
WT: Protocol/ project management, Data collection or manage-
ment, Manuscript writing/editing.
AK: Protocol/ project management, Data collection or management,
Manuscript writing/editing.
Acknowledgement
This review was registered in PROSPERO (CRD42019123546). We
would like to thank Mr. Bryan Allan for his language input in proof-
reading this manuscript. No external funding and no competing inter-
ests declared.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.jclinane.2019.06.027.
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