Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial
Martinez et al. Trials
Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial
F. Eduardo Martinez 0
0 Intensive Care Unit, Department of Anaesthesia, Intensive Care and Pain Medicine, John Hunter Hospital , Lookout Road, New Lambton Heights, NSW 2305 , Australia
Background: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium. Methods: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep. Discussion: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU.
Delirium; Melatonin; Intensive care unit; Sleep
Trial registration: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471.
Registered on 20 December 2015.
Delirium is a state of acute organic brain dysfunction
with fluctuating disturbances of attention and cognition
which occurs as a direct consequence of an underlying
medical condition . It is particularly common in
patients in intensive care units (ICUs), with a wide range
of prevalence ranging between 11% and 83% reported in
the literature [2–5]. Researchers in a multi-centre study
that included one of the participating hospitals of this
trial reported a delirium prevalence of 45% , whereas
a preliminary audit for this trial at the two primary sites
demonstrated a delirium prevalence of 52% when
evaluating patients with an expected ICU length of stay (LOS)
of more than 24 h.
Delirium in intensive care is associated with worse
outcomes. These include higher mortality (estimated as a 10%
increase in the relative risk of death for each day of
delirium) [6–10], more time on a ventilator [9–11], unplanned
removal of tubes and catheters , increased use of
physical restraints , increased requirement for
tracheostomy, greater post-operative complications , poorer
functional status, cognitive impairment [7, 9, 13, 14],
increased hospital and ICU LOSs [8, 11, 12], increased
medical costs , higher risk of dementia [7, 13] and
greater likelihood of admission to residential care .
The aetiology of delirium is multi-factorial . In the
critical care setting, it is likely that disturbances of sleep
and of the normal circadian rhythm play a significant
role . Sleep deprivation may occur as a result of
environmental disturbances, loss of normal day-night
routine, critical illness itself and patient treatments.
However, although sleep disturbances have been
demonstrated to predispose individuals to post-operative
delirium, sleep problems and their relationship to delirium in
ICU remain relatively unexplored [18, 19].
In the clinical setting delirium can be approached with
prevention strategies or treatment strategies, with the
former appearing to be more effective. Authors of a
recent meta-analysis  reported 8 of 15 preventative
studies were successful, compared with 1 of 10
treatment studies, in terms of reducing delirium incidence
and duration. There are several non-pharmacological
strategies used for preventing delirium in ICU, but there
are no pharmacological strategies that are used routinely
[6, 20]. Reasons for this include a lack of clear evidence,
limited pathophysiological understanding, potential side
effects, cost and difficulties identifying which patients
will benefit [21, 22].
Good-quality sleep at night is rapidly being recognised
as an important aspect of delirium prevention .
Melatonin is a natural hormone secreted by the pineal
gland, which helps in the regulation of the sleep-wake
cycle . It is stimulated by low light, peaking during
the main sleep period [24–26]. Melatonin can be given
exogenously. In healthy volunteers, it decreases sleep
onset latency, increases sleep efficiency and increases total
sleep duration . It also increases the duration of
rapid eye movement (REM) sleep, which is thought to
have a positive effect on health and healing . It is
inexpensive, has an excellent safety profile and is widely
used in the community [29–31]. Critical illness causes
deregulation of melatonin secretion by the pineal gland,
and light and darkness fail to restore its normal pattern
of secretion [32, 33]. Serum melatonin levels are found
to be lower after surgery, in delirious post-surgical
patients and in those receiving opioids [25, 34]. Studies
have also demonstrated that exogenous melatonin is well
absorbed enterally in critically ill patients .
Melatonin has previously been evaluated for the
treatment of delirium, but only five trials have put it to the
test as a prophylactic agent. Sultan and colleagues 
evaluated prophylactic melatonin in patients requiring
elective hip replacement surgery and found a significant
decrease in delirium in the group receiving melatonin.
Al-Aama and colleagues  compared prophylactic
melatonin with placebo in a population of acutely ill
elderly patients and found that melatonin was associated with
a reduction in the incidence of delirium. De Jonghe and
colleagues [38, 39] evaluated the effect of prophylactic
melatonin versus placebo on the incidence of delirium in
patients requiring hip surgery and found no significant
difference. Hatta and colleagues  compared the
melatonin receptor agonist ramelteon prophylactically with
placebo in critically ill medical patients and found a
significant reduction in delirium in the ramelteon group.
Artemiou and colleagues  evaluated the use of
prophylactic melatonin in patients undergoing cardiac surgery.
They reported a delirium incidence of 8.4% versus 250
control patients in whom the incidence was 20.8%.
However, there was no placebo in their trial, and the trial was
Rationale for proposed study
Delirium is common in ICU; it is associated with worse
outcomes when it occurs; and currently there are limited
therapies to prevent it. The studies evaluating melatonin as
a prophylactic agent suggest that melatonin could play an
important role in preventing delirium in the critically ill
. However, these studies were small and conducted
with populations that do not include ICU patients. It is
unclear whether these proposed benefits would be replicated
in an adequately powered, randomised controlled trial or if
they would translate to critical care. In the present study,
we will attempt to answer the question whether, in a
population of critically ill adults, prophylactic melatonin,
compared with placebo , decreases the prevalence, duration
and severity of delirium.
The primary objective of this trial will be to determine
whether melatonin given prophylactically decreases the
prevalence of delirium in critically ill patients. The
secondary objectives will be to determine whether
prophylactic melatonin decreases the severity and
duration of delirium, improves sleep quality, reduces
hospital and ICU LOS, improves morbidity and
mortality, and reduces healthcare costs through reduced LOS
and intensity of medical therapy.
This study will be a prospective, multi-centre,
randomised, placebo-controlled, double-blind, prophylactic
intervention trial of melatonin 4 mg versus placebo
given at 21:00 for 14 days or until ICU discharge to
critically ill patients admitted to ICU with an expected ICU
LOS of at least 72 h (two arms, 1:1 allocation, parallel
design). A subgroup of 100 patients from the two main
research sites (Sir Charles Gairdner Hospital and John
Hunter Hospital) will also undergo polysomnographic
Patients admitted to a participating ICU identified by
the treating intensivist as having an expected total ICU
LOS of 72 h or more are eligible. Patients must be
enrolled within 48 h of their ICU admission and receive
the first dose of the study drug on the day of enrolment.
The exclusion criteria are patients younger than 18 years
of age; patients already receiving melatonin therapy
before their admission to ICU; prior hypersensitivity
reaction to any of the components (sucralose and glycerol)
of the study drug; patients expected to be discharged
within 72 h of admission; expected/inevitable death
within 48 h of enrolment; pregnancy or breastfeeding;
patients who are non-English-speaking; patients whose
condition is not expected to improve adequately for
them to be able to be assessed with a Confusion
Assessment Method for the ICU (CAM-ICU) score during
their ICU stay; patients who are not able to be assessed
because of neurological problems that would affect their
ability to participate in CAM-ICU assessment (as judged
by the treating physician); no enteral route/nil by mouth
(melatonin is not available in intravenous formulation);
and hepatic impairment, defined as alanine
aminotransferase greater than 500 IU/L, previous liver transplant or
liver cirrhosis of Child-Pugh classes B and C.
Eligible participants will be randomised to receive
melatonin 4 mg or placebo at 21:00 for 14 consecutive nights
or until ICU discharge, whichever occurs first. This will
be given either orally or via nasogastric tube, depending
on the circumstances. All concomitant care and
interventions that are normal practice for the ICU or based
on other trials are permitted.
A subset of 100 patients will also undergo two episodes
of polysomnographic testing overnight on days 2–3 and
days 5–7 of their ICU stay. This will occur only at the two
primary sites: Sir Charles Gairdner Hospital and John
All assessors using the CAM-ICU and the Confusion
Assessment Method for delirium severity (CAM-S) will
receive training in these assessment tools along with
regular monitoring to ensure the tools are being applied
reliably. The primary outcome will be prevalence of
delirium. This will be measured and reported as delirium-free
assessments. The secondary outcomes will be (1) overall
prevalence of delirium, (2) duration of delirium, (3)
severity of delirium, (4) sleep quality, (5) ICU and hospital
LOS, (6) morbidity and mortality and (7) healthcare costs.
Prevalence of delirium
The primary outcome will be the proportion of
delirium-free assessments as measured by the
CAMICU score. Prevalence rather than incidence has been
chosen because delirium on admission to ICU may not
be measureable, owing to many patients being intubated
and sedated and therefore unable to be assessed. Where
possible, we will measure baseline delirium and provide
an incidence in those patients. The CAM-ICU is widely
used and is the best-performing of the tools adapted for
use in ICU by non-psychiatrists, with a pooled sensitivity
of 80.5% and specificity of 95.9% [43, 44]. The
CAMICU will be used twice daily with all assessable patients
while they are receiving the study drug for 14 days or
until ICU discharge, whichever occurs sooner.
Secondary outcomes will include the following:
1. Overall prevalence of delirium: Patients will be diag
nosed as delirious when they have at least one positive
CAM-ICU up to ICU discharge or day 14 after
enrolment if still in ICU.
2. Duration of delirium: Once the diagnosis of delirium is
made, duration will be recorded as how many subsequent
days on which they have a positive CAM-ICU until ICU
discharge or day 14 after enrolment.
3. Severity of delirium: Severity will be assessed using
the CAM-S Short Form , which gives a score from 0
to 8. Considering that sleep is an important part of this
study, an additional question from the CAM-S Long
Form on the sleep-wake cycle has been included in the
assessment. Thus, a score from 0 to 10 will be recorded.
Indirect markers of delirium severity will also be
recorded daily until ICU discharge or day 14 after
enrolment. These are (1) need for anti-psychotics or sedation
(total daily doses will be calculated); (2) need for physical
restraints; (3) patient participation in physiotherapy
sessions and mobilisation; and (4) patient removal of
intravenous lines, drains or catheters.
Sleep quality will be measured by (1) daily
patient/nurserated sleep assessment (Richards-Campbell Sleep
Questionnaire) while in ICU  and (2) patient-rated sleep
quality questionnaire after ICU discharge . This will
be performed from 2 to 14 days after ICU discharge with
the timing dependent on the patient’s ability to participate.
Patients unable to participate will be omitted.
A subgroup of 100 patients will undergo sleep quality
assessments twice during their ICU stay using
polysomnography. The hypothesis is that melatonin will increase
the quality and quantity of sleep compared with placebo.
These 100 patients will come only from either Sir
Charles Gairdner Hospital or John Hunter Hospital.
Patients included in the study at these sites will be
sequentially allocated to the subgroup. Polysomnography
will be done between days 2 and 3 and between days 5
and 7 of the ICU stay. For logistical reasons, we will
have limited access to polysomnography. It will be
available only from Monday through Thursday, and hence we
have not been able to randomise patients to this
investigation. It is expected that, by virtue of blinding and
randomisation, approximately 50% of patients will be from
the melatonin arm and 50% from the placebo arm. The
polysomnography protocol and reporting have been
standardised and agreed upon by senior sleep physicians
at the two main centres. Patients will not be in a single
room every time polysomnography is performed,
because this is a pragmatic study and will reflect
realworld conditions as much as possible. Many
participating units do not have single rooms for all of their
patients. The range of days is selected so that if patients
cannot undergo polysomnography because of
procedures, they could have it the following night. If
polysomnography needs to be aborted, we will try to repeat it
within that range of days. This will aid in the
understanding of sleep patterns in the critically ill and the
biological mechanisms through which melatonin may work.
Several parameters will be generated by the sleep
studies. Two sleep experts involved in the study design have
selected the following four variables as the most
important (each will be a secondary outcome): (1) total sleep
time, (2) sleep efficiency, (3) percentage REM sleep and
(4) arousal index.
Morbidity and mortality
Standard ICU markers of morbidity and mortality will
be recorded on a daily basis until ICU discharge or day
14 after enrolment. These include (1) duration of
mechanical ventilation measured as ventilator-free days; (2)
daily need for vasopressor use; (3) daily need for renal
replacement therapy; (4) re-intubation, delayed
extubation or need for tracheostomy; (5) Sequential Organ
Failure Assessment score for injury severity; (6) mortality at
28 and 90 days; and (7) destination after ICU discharge.
Participant timeline and recruitment
Patients will be screened on the morning handover for
eligibility. Baseline data will be recorded on day 0.
Patients will be assessed each day and have the primary
and secondary outcomes recorded daily until ICU
discharge or day 14 after enrolment. Patients will be seen
on the ward between days 2 and 14 after ICU discharge
to complete the sleep questionnaire. Patients who have
been discharged home will be contacted by phone.
Patients will be followed through their hospital stay to
record ICU LOS, hospital LOS, and 28- and 90-day
mortality. The trial assessment schedule is displayed in
Table 1 and Fig. 1.
To allow for accurate recording of LOS, we will allow
for a 6-month period after the last patient is enrolled. If
there are patients still hospitalised at that point, the last
day of the 6-month period will be recorded to calculate
as their last day of hospital admission.
On the basis of two sample size calculations, with an
alpha value of 0.05 and a power of 80%, a total of 850
patients will be recruited into the study, with 425
patients in each arm. Estimates of sample size were
made on the basis of percentage of delirium-free
assessments (the primary outcome). An audit of 100 patients
Table 1 Time schedule of Pro-MEDIC enrolment, interventions and assessments
Days 2–14 Hospital
post-ICU discharge discharge
Use of physical restraints
Assessment of sleep quality
ICU and hospital LOS
Hospital discharge destination
Mortality at 28 and 90 days
CAM-S test (for patients found to be delirious) X
Record daily ICU interventions
Record daily anti-psychotic and sedation use
Record daily sleep aid measures
X (days 0, 5 and 10)
Abbreviations: CAM-ICU Confusion Assessment Method for the ICU, CAM-S Confusion Assessment Method for delirium severity, ICU Intensive care unit, LOS Length
of stay, Pro-MEDIC Prophylactic Melatonin for Delirium in Intensive Care, RCSQ Richards-Campbell Sleep Questionnaire
at Sir Charles Gairdner Hospital and John Hunter Hospital
was used to obtain preliminary data to guide sample size
calculations where an average of 54% of assessments were
deemed delirium-free (SD 45%). The research group is
aiming to detect a 10% increase in the percentage of
deliriumfree assessments. This would give us a sample size
calculation of 319 per group. Adjustment for a non-parametric test
(15%) increases this to 367 per group. It is expected that up
to 10% of patients recruited into the study will not be
assessable for delirium at any point during the study. To account
for this and for missing data/loss to follow-up, the sample
size was increased by 15% to 423 patients per group (total
rounded to 850). This sample size will also be sufficient to
analyse the secondary measures.
To prevent and treat the issue of likely missing data,
the follow-up period for the primary outcome is short
and data collection is electronic, with out-of-range and
missing alerts. There will be documentation of why data
are missing. This will help us to formulate reasonable
assumptions about observations that are missing .
To achieve adequate recruitment numbers, there will be
frequent reminders to the participating sites, and
progress reports will be scheduled periodically.
Allocation, randomisation, compliance and blinding
Patients will be randomised to melatonin or placebo in a 1:1
ratio according to a computer-generated randomisation list,
stratified by site, with standard block sizes of six. An
independent statistician other than the statistician
analysing the data will create the allocation sequence. This
randomisation list will be provided by the independent
statistician directly to the compounding pharmacy.
Each patient’s bottle will be labelled with a site-specific
randomisation number, which will become that patient’s
study number. Study sites will administer the content of
the study drug bottles sequentially to patients in the order
in which they are included in the study.
Each participating site’s principal investigator or research
coordinator will enrol patients. All patients will receive the
same interventions, except for the sleep studies, which will
be assigned by the principal investigators at the two sites
performing sleep studies. A flowchart of enrolment,
allocation, follow-up and analysis is shown in Additional file 1.
When a patient is enrolled in the study, ‘Pro-MEDIC
study drug’ will be charted on the medication chart. The
ICU bedside nurse, using an oral/enteral syringe, will
administer the study drug at 21:00 until discharge from
ICU or 14 days after enrolment, whichever occurs first.
The study drug will be prepared by a single private
compounding pharmacy that currently produces
melatonin suspension for the health department and has
extensive experience in clinical trials. They will be given
the randomisation list and will prepare individual bottles
for each patient that will contain an amount of the study
Fig. 1 Time schedule of Prophylactic Melatonin for Delirium in Intensive
Care (Pro-MEDIC) enrolment, interventions and assessments. CAM-ICU
Confusion Assessment Method for the ICU, CAM-S Confusion Assessment
Method for delirium severity, ICU Intensive care unit, LOS Length of stay
drug to last for up to 14 days. Both melatonin and
placebo will be made to look and taste the same. The
melatonin will be prepared as a 2 mg/ml solution. The drug
packs will be shipped from the compounding pharmacy
to each of the participating sites, and responsibility will
be assigned to the site’s principal investigator.
The shelf life of the melatonin suspension is
12 months. The project manager will co-ordinate with
the pharmacy to ensure sites have an adequate supply of
the study drug based on recruitment rates. Subjects may
withdraw their consent to participate in the study at any
time and for any reason.
Compliance will be indicated by the nurse’s signature
on the medication chart each day that the study drug is
administered to the patient. There will be no restriction
or change in the use of any sedative, analgesic or
antipsychotic agents given, but the use of these medications
will be recorded.
The patients, the investigators, and the ICU doctors
and nurses looking after patients enrolled in the study
will be blinded to the treatment that patients are
receiving. Only the independent statistician providing the
allocation list to the pharmacy, the compounding pharmacy,
and the independent data and safety monitoring
committee (DSMC), should they need to investigate an
adverse event (AE), will know which is melatonin and
which is placebo.
A standardised process for unblinding will be in place
for all sites. Blinding will be broken only if the senior
treating ICU doctor feels that the drug is causing AEs to
the patient and it is necessary to know if the patient
received melatonin, such as in the case of anaphylaxis.
Other AEs may lead to cessation of the study drug but
would not be expected to require unblinding.
Data collection and management
Data will be collected and entered into a REDCap© 
electronic database behind a secure firewall. The
REDCap system will perform data entry validation. For the
non-primary sites, data can be entered into the REDCap
database, or the case report forms can be filled in
manually and forwarded to the primary sites. Strict
confidentiality and privacy will be kept at all times. The data will
be stored in password-protected files and will be kept
for 15 years. The final database will be locked after all
information for the last patient has been entered and
provided to the statistician.
If a participant withdraws consent, the investigators
will ask permission to retain all data collected up to the
point of withdrawal and to collect survival status and
discharge destination data. If subjects cease the study
drug for any reason, data will still be collected and
interpreted in an intention-to-treat analysis. The reason for
withdrawal will be recorded. No attempt will be made to
replace patients who withdraw from the study.
Analyses will be conducted on both intention-to-treat
and per-protocol bases. All outcomes will be analysed
for superiority (two-sided) and considered statistically
significant at the 5% level. Baseline data will be recorded
and analysed for imbalances between the treatment
groups. The primary endpoint, percentage of
deliriumfree assessments, will initially be analysed using a
MannWhitney U test to compare the two treatment arms.
Subsequent supporting analyses will be carried out using
a negative binomial model with adjustments made for
number of assessments (accounting for withdrawals),
important covariates and baseline data where
appropriate. Secondary endpoints of any prevalence of delirium
during the 14 days and duration of delirium from first
onset will be analysed using a chi-square test with
supporting analyses of binary and ordinal logistic regression,
respectively, allowing adjustments for covariates. Sleep
quality analysis based on the Richards-Campbell Sleep
Questionnaire on each of days 2–14, the patient-rated
sleep questionnaire completed after day 14, and sleep
measurements derived from polysomnography done on
days 2–4 and 5–7 (total sleep time, sleep efficiency,
REM sleep percentage and arousal index) will all be
analysed initially using a Mann-Whitney U test to compare
the two treatment arms and subsequently using linear
mixed models with fixed factors of treatment time and
their corresponding interaction, along with random
patient effects. ICU LOS, total hospital LOS, mortality and
morbidity events will be analysed initially using
KaplanMeier curves and log-rank tests and subsequently using
Cox proportional hazards models. Individuals withdrawn
from the study early will be censored at the date of
withdrawal. Specific subgroup analysis of major outcomes
will be carried out, stratifying by age, sex, delirium
medical subgroup and delirium risk as per the prediction of
delirium in ICU patients (‘PRE-DELIRIC’) score. A fully
specified statistical analysis plan will be finalised and
approved by statisticians at the two main hospitals before
the database is unlocked and opened. Data analysis is to
be carried out using the R software programme .
Data monitoring and safety
A DSMC will be made up of an independent intensivist,
an epidemiologist and a statistician. They will confer
after 100 patients have been enrolled and will review the
unblinded data to determine the need for early
termination of the trial. Early termination will be decided on
the basis of either (1) safety concerns with the ongoing
review of all severe adverse events (SAEs) and suspected
unexpected severe adverse reactions (SUSAR) or (2)
outstanding benefits. The DSMC will report to the research
committee and make a recommendation after its review.
A similar interim analysis will be performed at the
midpoint of the study after enrolment of 400 patients.
The Haybittle-Peto stopping rule will be used in both
analyses. Thus, if there is a probability of less than 0.001 in
either direction that the treatment and placebo are different,
the DSMC will recommend that the study be ceased.
Melatonin has no serious adverse reactions
documented in the medical literature . An AE caused by
either melatonin or its solution will be considered as any
untoward medical occurrence in a patient enrolled in
this study, regardless of its causal relationship to the
study treatment. AEs will be monitored with a checklist
of symptoms commonly associated with medications,
including headache, gastrointestinal symptoms, lethargy,
myalgias and skin symptoms.
Melatonin has a very safe therapeutic profile.
Assessment and documentation of AEs will be carried out by
the principal and associate investigators and will be
included in the data collection instrument. Once collected,
these will be reviewed and classified as AEs, SAEs or
SUSARs. The DSMC will have access to this information
as unblinded data.
The baseline mortality of ICU patients enrolled in trials
will be high because of the critical illness necessitating
admission. New organ failure in a high proportion of ICU
patients is not unexpected, regardless of optimal
treatment and study intervention. As such, and in keeping with
the advice of Cook and colleagues, events that are part of
the natural history of the primary disease process or
expected complications of critical illness will not be reported
as SAEs in this trial unless they are thought to be causally
related to the study intervention .
Ethics and dissemination
Ethics approval has been sought and obtained from the
Sir Charles Gairdner Hospital Human Research Ethics
Committee in Western Australia and the Hunter New
England Human Research Ethics Committee in New
South Wales. The NSW Civil and Administrative
Tribunal (NCAT) has granted approval to conduct the clinical
trial in this state. Protocol amendments will be
communicated to these ethics committees for approval.
Subject confidentiality is strictly held in trust by the
investigators and is extended to clinical data collected
and test results. No information will be released to any
third party without the prior written approval of the
participating institutions. Clinical data will not be
released without the written permission of the
participating individuals, except for the DSMC where required.
Data will be identified only by the study’s subject
This study protocol has been written following the
Standard Protocol Items: Recommendations for
Interventional Trials (SPIRIT) checklist (Additional file 1). A
populated checklist (Table 1) and a figure (Additional
file 1) displaying the schedule of enrolment,
interventions and assessments have been provided. The results
of this trial will be written as an article that will be
submitted to peer-reviewed medical journals for publication.
Informed consent will be obtained from the patients or,
when it is not possible for patients to consent for
themselves, from their person responsible. The investigators
received approval from the NCAT to allow the inclusion
of patients who are highly dependent on medical care.
In Western Australia, the study will be undertaken using
an emergency waiver of consent, as allowed for in the
National Health and Medical Research Council national
statement, in conjunction with acknowledgement from
the patient’s person responsible that he or she is not
aware of any reason why the patient would have chosen
not to participate. All patients will be followed and given
the opportunity to consent to continue in the study once
their capacity to consent is regained .
Delirium is increasingly being recognised as a significant
issue in hospital and particularly in ICU. It is associated
with poorer outcomes for the patients, their families and
the wider community. Intensive care is an area where
the prevalence of delirium is higher than in the general
wards. There are multiple potentially modifiable risk
factors but very limited effective pharmacological options
for either prevention or treatment.
To our knowledge, this trial will be the largest trial
evaluating melatonin as a prophylactic agent for
delirium in any setting, and certainly the largest in intensive
care. It will also be one of the larger trials evaluating any
prophylactic agent in intensive care. Currently, a trial by
van den Boogaard and colleagues is recruiting. They are
evaluating haloperidol as a preventative agent for ICU
delirium and plan to enrol 2145 patients into 3 arms.
However, haloperidol has potential side effects, whereas
melatonin is extremely safe, inexpensive and potentially
more acceptable to patients, with the rate of side effects
being less than placebo .
The polysomnography arm will be an insightful
explanatory component of the study and, to our knowledge, will
be one of the largest series of polysomnography in the
ICU setting. It may open up further avenues for research
into sleep in critical care.
The choice of 4 mg of melatonin as a dose required
some consideration. The existing trials have used a
variety of doses ranging from 0.5 mg to 5 mg [37–39, 41].
Bourne and colleagues  used 10 mg to aid sleep and
found a carry-over effect to the following day. Therefore,
we feel that 4 mg is a practical dose within the range of
previous studies. Evidence exists confirming absorption
in critical care for similar doses, and this dose is unlikely
to have a significant carry-over effect the following day.
Melatonin (Circadin; Flynn Pharma, Dublin, Ireland),
the current Pharmaceutical Benefits Scheme listed agent,
also comes in 2-mg tablets.
Patients will be assessed for delirium on enrolment.
This will not be possible where patients arrive at the unit
ventilated and heavily sedated. Because of this, true
incidence will not be able to be established, and it is
recognised that some patients may already have delirium on
enrolment. The investigators feel it is important to keep
this a pragmatic trial. The decision to mandate that
patients be enrolled within 48 h of their ICU admission
was made to ensure that the study drug is given early in
The enrolment of patients who have an expected LOS
longer than 72 h is being done because patients with
increased LOS are more likely to develop delirium.
Although prediction tools for delirium do exist [55, 56],
they are complex, and we seek to maintain the
generalisability of our findings to a broad range of ICU patients.
Additional file 1: SPIRIT 2013 checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 121 kb)
AE: Adverse event; CAM-ICU: Confusion Assessment Method for the ICU;
CAM-S: Confusion Assessment Method for delirium severity; CRF: Case report
form; D/C: Discharge; DSMC: Data and safety monitoring committee;
ICU: Intensive care unit; LOS: Length of stay; NCAT: NSW Civil and
Administrative Tribunal; PRE-DELIRIC: Prediction of delirium in ICU patients;
Pro-MEDIC: Prophylactic Melatonin for Delirium in Intensive Care;
RCSQ: Richards-Campbell Sleep Questionnaire; REM: Rapid eye movement;
SAE: Severe adverse event; SPIRIT: Standard Protocol Items:
Recommendations for Interventional Trials; SUSAR: Suspected unexpected
severe adverse reaction
We acknowledge Dr. Richard Norman for statistical and database support, as
well as Erina Myers, who is the newly appointed project manager for this
trial. We also acknowledge Dr. Paul Woods, director of the ICU at Sir Charles
Gairdner Hospital, and Dr. Ken Havill, director of the ICU at John Hunter
Hospital, for their support.
Funding and resources for this study come from the State Health Research
Advisory Council Grant of Western Australia in the form of AUD$264,800 and
from the John Hunter Hospital Charitable Trust Research Grant in the form of
AUD$21,745. The funding bodies have had no role in designing the trial.
Availability of data and materials
There are no data from which conclusions have been made in this article.
FEM, BW and MA are responsible for the idea for the study and creating the
original protocol. AF has provided substantial expertise in the area of delirium. BR
and MHa have provided expertise in study processes and logistics. EK and KM have
been responsible for statistical input and database creation and management. RP
and LC have been responsible for pharmacological input and expertise. DH, BS and
MHe have been responsible for input on the areas of sleep and logistics for
polysomnography. All authors read and approved the final manuscript.
F. Eduardo Martinez, MD, FCICM, chief investigator, project coordinator;
Matthew Anstey, MBBS, MPH, FACEM, FCICM, PGDipEcho, chief investigator,
project coordinator; Andrew Ford, MBBS, FRANZCP, assist with coordinating
and reviewing of results, expertise in delirium; Brigit Roberts, RN, ICU
certification, project and data management, screening participants, data
collection; Miranda Hardie, RN, MClinEp, project and data management,
screening participants, data collection; Robert Palmer, BPharm,
GradDipClinPharm, pharmacy expertise and input, overseeing drug
dispensing; Lynn Choo, MScPharmPrac, BPharm, MSHP, MRPharmS, advanced
practice pharmacist, pharmacy expertise and input, overseeing drug
dispensing; David Hillman, MBBS, FANZCA, input on sleep and
polysomnography, performance and interpretation of polysomnography;
Michael Hensley, MB BS, PhD, FRACP, input on sleep and polysomnography,
performance and interpretation of polysomnography; Erin Kelty, BSc,
MBioStat, statistical analysis, data management; Kevin Murray, BSc, MSc, PhD,
database and statistical support; Bhajan Singh, MBBS, FRACP, PhD, input on
sleep and polysomnography, performance and interpretation of
polysomnography; Bradley Wibrow, MBBS, FACEM, FCICM, chief investigator,
Ethics approval and consent to participate
Ethics approval was obtained from the Sir Charles Gairdner Hospital Human
Research Ethics Committee (approval number 2015-122) and the Hunter New
England Human Research Ethics Committee (approval number 16/03/16/3.03).
In the state of New South Wales, Australia, an application has been made to the
NSW Civil and Administrative Tribunal to conduct this study of patients who are
highly dependent on medical care. Consent will be obtained from the patients
or, when they are unable to consent for themselves, from the patient’s person
responsible. All patients will be followed and given the opportunity to consent
for themselves when their ability to do so has been regained.
1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders . 5th ed. Washington, DC: American Psychiatric Association ; 2013 .
2. Ouimet S , Kavanagh BP , Gottfried SB , Skrobik Y . Incidence, risk factors and consequences of ICU delirium . Intensive Care Med . 2007 ; 33 ( 1 ): 66 - 73 .
3. Devlin JW , Roberts RJ , Fong JJ , Skrobik Y , Riker RR , Hill NS , et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study . Crit Care Med . 2010 ; 38 ( 2 ): 419 - 27 .
4. Girard TD , Pandharipande PP , Carson SS , Schmidt GA , Wright PE , Canonico AE , et al. Feasibility , efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial . Crit Care Med . 2010 ; 38 ( 2 ): 428 - 37 .
5. Ely EW , Gautam S , Margolin R , Francis J , May L , Speroff T , et al. The impact of delirium in the intensive care unit on hospital length of stay . Intensive Care Med . 2001 ; 27 ( 12 ): 1892 - 900 .
6. Skrobik Y. Delirium prevention and treatment . Crit Care Clin . 2009 ; 25 ( 3 ): 585 - 91 .
7. Witlox J , Eurelings LS , de Jonghe JF , Kalisvaart KJ , Eikelenboom P , Van Gool WA . Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis . JAMA . 2010 ; 304 ( 4 ): 443 - 51 .
8. Trogrlić Z , van der Jagt M , Bakker J , Balas MC , Ely EW , van der Voort PH , et al. A systematic review of implementation strategies for assessment, prevention, and management of ICU delirium and their effect on clinical outcomes . Crit Care . 2015 ; 19 : 157 .
9. Cavallazzi R , Saad M , Marik PE . Delirium in the ICU: an overview . Ann Intensive Care . 2012 ; 2 ( 1 ): 49 .
10. van den Boogaard M , Schoonhoven L , van der Hoeven JG , van Achterberg T , Pickkers P. Incidence and short-term consequences of delirium in critically ill patients: a prospective observational cohort study . Int J Nurs Stud . 2012 ; 49 ( 7 ): 775 - 83 .
11. Mehta S , Cook D , Devlin JW , Skrobik Y , Meade M , Fergusson D , et al. Prevalence , risk factors, and outcomes of delirium in mechanically ventilated adults . Crit Care Med . 2015 ; 43 ( 3 ): 557 - 66 .
12. McKhann GM , Grega MA , Borowicz Jr LM , Bechamps M , Selnes OA , Baumgartner WA , et al. Encephalopathy and stroke after coronary artery bypass grafting: incidence, consequences, and prediction . Arch Neurol . 2002 ; 59 ( 9 ): 1422 - 8 .
13. Saczynski JS , Marcantonio ER , Quach L , Fong TG , Gross A , Inouye SK , et al. Cognitive trajectories after postoperative delirium . N Engl J Med . 2012 ; 367 ( 1 ): 30 - 9 .
14. Wolters AE , van Dijk D , Pasma W , Cremer OL , Looije MF , de Lange DW , et al. Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study . Crit Care . 2014 ; 18 ( 3 ): R125 .
15. Milbrandt EB , Deppen S , Harrison PL , Shintani AK , Speroff T , Stiles RA , et al. Costs associated with delirium in mechanically ventilated patients . Crit Care Med . 2004 ; 32 ( 4 ): 955 - 62 .
16. Salluh JI , Soares M , Teles JM , Ceraso D , Raimondi N , Nava VS , et al. Delirium epidemiology in critical care (DECCA): an international study . Crit Care . 2010 ; 14 ( 6 ): R210 .
17. Delaney LJ , Van Haren F , Lopez V. Sleeping on a problem: the impact of sleep disturbance on intensive care patients - a clinical review . Ann Intensive Care . 2015 ; 5 : 3 .
18. Shehabi Y , Bellomo R , Reade MC , Bailey M , Bass F , Howe B , et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients . Am J Respir Crit Care Med . 2012 ; 186 ( 8 ): 724 - 31 .
19. Bellapart J , Boots R. Potential use of melatonin in sleep and delirium in the critically ill . Br J Anaesth . 2012 ; 108 ( 4 ): 572 - 80 .
20. Serafim RB , Bozza FA , Soares M , do Brasil PE , Tura BR , Ely EW , et al. Pharmacologic prevention and treatment of delirium in intensive care patients: a systematic review . J Crit Care . 2015 ; 30 ( 4 ): 799 - 807 .
21. Clegg A , Young JB . Which medications to avoid in people at risk of delirium: a systematic review . Age Ageing . 2011 ; 40 ( 1 ): 23 - 9 .
22. Siddiqi N , Stockdale R , Britton AM , Holmes J. Interventions for preventing delirium in hospitalised patients . Cochrane Database Syst Rev . 2007 ; 2 : CD005563 .
23. Pandi-Perumal SR , Trakht I , Srinivasan V , Spence DW , Maestroni GJ , Zisapel N , et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways . Prog Neurobiol . 2008 ; 85 ( 3 ): 335 - 53 .
24. Lemoine P , Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia . Expert Opin Pharmacother . 2012 ; 13 ( 6 ): 895 - 905 .
25. Figueroa-Ramos MI , Arroyo-Novoa CM , Lee KA , Padilla G , Puntillo KA . Sleep and delirium in ICU patients: a review of mechanisms and manifestations . Intensive Care Med . 2009 ; 35 ( 5 ): 781 - 95 .
26. Olofsson K , Alling C , Lundberg D , Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients . Acta Anaesthesiol Scand . 2004 ; 48 ( 6 ): 679 - 84 .
27. Brzezinski A , Vangel MG , Wurtman RJ , Norrie G , Zhdanova I , Ben-Shushan A , et al. Effects of exogenous melatonin on sleep: a meta-analysis . Sleep Med Rev . 2005 ; 9 ( 1 ): 41 - 50 .
28. Kunz D , Mahlberg R , Müller C , Tilmann A , Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials . J Clin Endocrinol Metab . 2004 ; 89 ( 1 ): 128 - 34 .
29. van der Heijden KB , Smits MG , Van Someren EJW , Ridderinkhof KR , Gunning WB . Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleeponset insomnia . J Am Acad Child Adolesc Psychiatry . 2007 ; 46 ( 2 ): 233 - 41 .
30. Zhdanova IV , Wurtman RJ , Regan MM , Taylor JA , Shi JP , Leclair OU . Melatonin treatment for age-related insomnia . J Clin Endocrinol Metab . 2001 ; 86 ( 10 ): 4727 - 30 .
31. Cardinali DP , Srinivasan V , Brzezinski A , Brown GM . Melatonin and its analogs in insomnia and depression . J Pineal Res . 2012 ; 52 ( 4 ): 365 - 75 .
32. Perras B , Meier M , Dodt C. Light and darkness fail to regulate melatonin release in critically ill humans . Intensive Care Med . 2007 ; 33 ( 11 ): 1954 - 8 .
33. Mundigler G , Delle-Karth G , Koreny M , Zehetgruber M , Steindl-Munda P , Marktl W , et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis . Crit Care Med . 2002 ; 30 ( 3 ): 536 - 40 .
34. Shigeta H , Yasui A , Nimura Y , Machida N , Kageyama M , Miura M , et al. Postoperative delirium and melatonin levels in elderly patients . Am J Surg . 2001 ; 182 ( 5 ): 449 - 54 .
35. Bellapart J , Roberts JA , Appadurai V , Wallis SC , Nuñez-Nuñez M , Boots RJ . Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients . Clin Chem Lab Med . 2016 ; 54 ( 3 ): 467 - 72 .
36. Sultan SS . Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly . Saudi J Anaesth . 2010 ; 4 ( 3 ): 169 - 73 .
37. Al-Aama T , Brymer C , Gutmanis I , Woolmore-Goodwin SM , Esbaugh J , Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial . Int J Geriatr Psychiatry . 2011 ; 26 ( 7 ): 687 - 94 .
38. de Jonghe A , van Munster BC , Goslings JC , Kloen P , van Rees C , Wolvius R , et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial . CMAJ . 2014 ; 186 ( 14 ): E547 - 56 .
39. de Jonghe A , van Munster BC , van Oosten HE , Goslings JC , Kloen P , van Rees C , et al. The effects of melatonin versus placebo on delirium in hip fracture patients: study protocol of a randomised, placebo-controlled, double blind trial . BMC Geriatr . 2011 ; 11 : 34 .
40. Hatta K , Kishi Y , Wada K , Takeuchi T , Odawara T , Usui C , et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial . JAMA Psychiat . 2014 ; 71 ( 4 ): 397 - 403 .
41. Artemiou P , Bily B , Bilecova-Rabajdova M , Sabol F , Torok P , Kolarcik P , et al. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients . Kardiochir Torakochirurgia Pol . 2015 ; 12 ( 2 ): 126 - 33 .
42. Gupta U , Verma M. Placebo in clinical trials . Perspect Clin Res . 2013 ; 4 ( 1 ): 49 - 52 .
43. Ely EW , Inouye SK , Bernard GR , Gordon S , Francis J , May L , et al. Delirium in mechanically ventilated patients: validity and reliability of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) . JAMA . 2001 ; 286 ( 21 ): 2703 - 10 .
44. Gusmao-Flores D , Figueira Salluh JI , Chalhub RÁ , Quarantini LC . The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies . Crit Care . 2012 ; 16 ( 4 ): R115 .
45. Inouye SK , Kosar CM , Tommet D , Schmitt EM , Puelle MR , Saczynski JS , et al. The CAM-S: development and validation of a new scoring system for delirium severity in 2 cohorts . Ann Intern Med . 2014 ; 160 ( 8 ): 526 - 33 .
46. Richards KC , O'Sullivan PS , Phillips RL. Measurement of sleep in critically ill patients . J Nurs Meas . 2000 ; 8 ( 2 ): 131 - 44 .
47. Little A , Ethier C , Ayas N , Thanachayanont T , Jiang D , Mehta S. A patient survey of sleep quality in the intensive care unit . Minerva Anestesiol . 2012 ; 78 ( 4 ): 406 - 14 .
48. Little RJ , D'Agostino R , Cohen ML , Dickersin K , Emerson SS , Farrar JT , et al. The prevention and treatment of missing data in clinical trials . N Engl J Med . 2012 ; 367 ( 14 ): 1355 - 60 .
49. REDCap. https://projectredcap.org/. Accessed 2 Apr 2016 .
50. The R Project for Statistical Computing. R software. https://www.r-project. org/. Accessed 13 Apr 2016 .
51. Circadin [package insert] . Dublin, Ireland: Flynn Pharma. https://www. medicines.org.uk/emc/medicine/25643 and https://www.medicines. org.uk/ emc/PIL .27475.latest.pdf. Accessed 16 Dec 2016 .
52. Cook D , Lauzier F , Rocha MG , Sayles MJ , Finfer S. Serious adverse events in academic critical care research . CMAJ . 2008 ; 178 ( 9 ): 1181 - 4 .
53. National Health and Medical Research Council, Australian Research Council, Australian Vice-Chancellors' Committee. National statement on ethical conduct in human research (2007) - updated May 2015 . Canberra: Commonwealth of Australia; 2015 . https://www.nhmrc.gov.au/guidelinespublications/e72. Accessed 13 Apr 2016 .
54. Bourne RS , Mills GH , Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial . Crit Care . 2008 ; 12 ( 2 ): R52 .
55. van den Boogaard M , Pickkers P , Slooter AJ , Kuiper MA , Spronk PE , van der Voort PH , et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study . BMJ . 2012 ; 344 :e420.
56. van den Boogaard M , Schoonhoven L , Maseda E , Plowright C , Jones C , Luetz A , et al. Recalibration of the delirium prediction model for ICU patients (PRE-DELIRIC): a multinational observational study . Intensive Care Med . 2014 ; 40 ( 3 ): 361 - 9 .