Download Potential use of melatonin in sleep and delirium in the critically ill

British Journal of Anaesthesia 108 (4): 572–80 (2012)
doi:10.1093/bja/aes035
Potential use of melatonin in sleep and delirium
in the critically ill
J. Bellapart* and R. Boots
Burns, Trauma and Critical Care Research Centre, University of Queensland, Butterfield Street, Herston, QLD 4029, Australia
* Corresponding author. E-mail: [email protected]
Editor’s key points
† Sleep deprivation may be a
causal factor in intensive
care delirium in critically ill
patients.
† Melatonin is involved in
control of circadian rhythms
and sleep regulation.
† Melatonin may have a
potential therapeutic role in
intensive care unit patients.
† Further studies are required
before this can be
established.
Intensive care delirium is a well-recognized complication in critically ill patients. Delirium is
an independent risk factor for death in the intensive care unit (ICU), leading to
oversedation, increased duration of mechanical ventilation, and increased length of stay.
Although there has not been a direct causal relationship shown between sleep
deprivation and delirium, many studies have demonstrated that critically ill patients have
an altered sleep pattern, abnormal levels of melatonin, and loss of circadian rhythms.
Melatonin has a major role in control of circadian rhythm and sleep regulation and other
effects on the immune system, neuroprotection, and oxidant/anti-oxidant activity. There
has been interest in the use of exogenous melatonin as a measure to improve sleep.
However, there are only a few studies of melatonin in ICU patients and these use
heterogeneous methodologies. Therefore, it is not possible at this stage to make any
clear recommendations regarding the clinical use of melatonin in this setting. There is a
need for well-designed randomized controlled trials examining the role of melatonin in ICU.
Keywords: critical illness delirium; melatonin; polysomnography; sleep deprivation
Sleep abnormalities and acquired psychiatric disorders, such
as delirium, have been described extensively in critically ill
patients.1 – 3 Such conditions are common, affecting up to
60% of all intensive care unit (ICU) admissions.4 ICU delirium
is characterized by an altered level of consciousness and
abnormal behaviour patterns with an acute presentation
and a typical duration between 48 and 72 h. Risk factors
for ICU delirium include metabolic impairment,5 substance
withdrawal, severe sepsis, head injury,6 and premorbid pathologies, particularly chronic obstructive airway disease,
cognitive dysfunction,7 and sleep deprivation. The consequences of ICU delirium are an increase in ICU-related
morbidity such as prolonged stay,6 accidental extubation,
increased nosocomial infections, and injury to patients and
staff with associated increased ICU care costs.2 8 9
Strategies to control and reduce the severity of ICU delirium
are based on improved bedside environmental conditions,10 11
sedation algorithms designed to reduce the side-effects of
hypnotics or analgesics, and policies to improve sleep quantity
and quality.12 Interest in melatonin as a potential therapeutic
or prophylactic agent in the management of sleep disturbance
and potentially delirium in the ICU derives from demonstrated
low plasma concentrations and altered secretion patterns of
melatonin in the critically ill.13 However, a definitive therapeutic benefit of melatonin in the management of ICU
delirium has not been thoroughly investigated.
This review focuses on the physiological and pharmacological research relevant to critically ill patients with regard
to the potential clinical use of melatonin.
A systematic search of the PUBMED and MEDLINE databases was made using OVIDTM . In addition, searches were
made using Web of ScienceTM , EMBASETM , and the COCHRANE
database of systematic reviews. A MESH search used the key
words melatonin and (critically ill or intensive care unit) and
(delirium or agitation). All searches were then filtered for articles using English language and human adult populations
(.18 yr age) using either descriptive or experimental study
designs. Review articles, case reports, and clinical studies
were all included. The PUBMED and MEDLINE search identified 90 from 56 324 articles with EMBASE identifying 25
from 557 554 articles, Web of Science five from 12 articles,
and the Cochrane database one from 25 articles.
Endogenous melatonin physiology
Melatonin was first isolated in 1958, following studies of the
anatomical and physiological role of the pineal gland. Melatonin has been found integral to circadian rhythms and sleep
regulation in addition to effects on immune function, cell
growth, and other endocrine regulation. Clinically, melatonin
has been studied and used for a wide variety of sleep
disorders.14
Melatonin, or N-acetyl-methoxytryptamine, is synthesized
within the pinealocytes from the amino acid tryptophan
(Fig. 1). The rate-limiting enzyme is N-acetyltransferase
(AA-NAT) whose synthesis is promoted by darkness with its
activity modulated by multiple neuronal interactions,
& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA
Potential use of melatonin in sleep and delirium
Tryptophan
b-receptors
Nor epinephrine
+
+
5-Hydroxytryptophan
Serotonin
AMPc
(5-hydroxytriptamine)
+
5- Methoxytryptamine
N-acetyl serotonin
(5 hydroxy-N-acetyltriptamine)
(hydroxy Indole o -methyltransferase)
MELATONIN
(5-methoxy-N-acetyltriptamine)
Fig 1 Synthesis of endogenous melatonin. Sympathetic innervation of the pineal gland (specifically via norepinephrine) is the major transmitter involved in the synthesis of melatonin. Cyclic adenosine monophosphate (AMPc) activation acts as second messenger, stimulating
serotonin-N-acetyltransferase, to produce serotonin from tryptophan. While the availability of serotonin is a limiting factor in the synthesis
of melatonin, serotonin-N-acetyltransferase increases its activity 100-fold during darkness.
mainly based in the suprachiasmatic nuclei (SCN). Clockgenes (CLOCK and BMAL1) control the synthesis of melatonin
producing heteromeric complexes of two proteins (Period
and Cryptochrome, respectively) which in turn provide negative feedback for gene suppression.15 Although the pineal
gland is the main site for the synthesis of melatonin, other
sites such as the testis, retina, and the gastrointestinal
tract contribute, to a lesser extent, to the circulating levels
of melatonin.16 Endogenous melatonin is first released
around 6– 8 weeks after birth with peak secretion at 3 –5
yr,17 followed by a steady-state phase during puberty and a
progressive decline through adulthood.
Light induces AA-NAT proteolysis, leading to a rapid
decline in melatonin synthesis. Declining levels of these
clock-proteins trigger gene transcription and a new cycle of
melatonin synthesis with peak activation at night. The environmental cues that regulate an organism’s biological clock
are predominantly the daily alternation of light and darkness
acting via the retina and retino-hypothalamic pathways
directly on the SCN (Fig. 2). Melatonin secretion increases
directly with the length of darkness. Increased light intensity
both increases the quantity of endogenous melatonin produced and shifts the pattern of release throughout the circadian clock (melatonin synchronization). In blind people, there
is no synchronization of melatonin release, a state known as
‘free-running’.18
Endogenous melatonin is released at night beginning
around 21:00 with peak release between 2:00 and 4:00.
Melatonin release is inhibited typically between 7:00 and
9:00, coinciding with the peak of endogenous cortisol. The
average concentrations of melatonin in plasma are in the
order of 60 –70 pg ml21,19 with the oscillating melatonin
concentrations only derived from the pineal gland.20 The
principle metabolite of melatonin is 6-sulphatoxymelatonin
(MT6) with plasma concentrations of melatonin correlating
closely with urinary MT6 concentrations. The typical pattern
of MT6 excretion has a peak after midnight and a nadir in
the late afternoon but is subject to individual variability.
Sympathetic innervation is responsible for the rhythmic
secretion of endogenous melatonin with melatonin release
stimulated by norepinephrine via both b1 and a1 receptors.
Serotonin also has a receptor-modulating effect, but its
specific role remains uncertain.19
Biological effects of melatonin
Circadian rhythm
Circadian rhythms are set by an endogenous pacemaker in
the SCN21 and modulated by peripheral stimuli.22 While the
duration of light and dark cycles is the main environmental
triggers for shifting the phase of this pacemaker, oscillations
in the release of melatonin are the fundamental stimuli for
maintaining circadian rhythms. Melatonin outside the
central nervous system affects the end-organ effects of the
circadian rhythms via regulation of gene expression.22 In
humans, it is known that the peak of melatonin release correlates with the nadir of core temperature and alertness.23
However, despite the sleep induction effect of melatonin,
an inconsistent relationship exists between melatonin
spikes and EEG characteristics of sleep.
Adaptation to environmental changes and
neuroendocrine effects
Melatonin modulates seasonal changes in physiology, the
timing of puberty, core thermoregulation, and the fetal
perception of circadian rhythms.24 25 Melatonin stimulates
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Bellapart and Boots
Retinal receptors
Activation of Melanopsin
+
Retino-hypotalamic pathway
+
+
Suprachiasmatic nucleous
Circadian pacemaker
Paraventricular nucleous
Light
Darkness
+
Superior cervical ganglia
+
+
+
Post-ganglionic sympathetic
Release of Serotonin
SEROTONIN
+
PINEAL GLAND
MELATONIN
Accumulates inside pinealocytes
during daylight
+
Intracrine
effects
Autocrine
effects
Paracrine effects
Fig 2 Physiological pathways for the synthesis of melatonin. Direct light activates melanopsin (a photo-pigment within the retina), leading to
pupillary constriction, suppression of circadian rhythms, photo-entrainment, regulation of alertness, and cognitive functions with suppression
of the release of melatonin. Light inhibits the release of melatonin from the pineal gland and promotes its storage after formation during dark
cycles. Darkness stimulates post-ganglionic serotonin which directly stimulates the release of melatonin from the pineal gland.
the secretion of prolactin from the pituitary26 and increases
luteinizing hormone (LH) pulses.25 High doses of melatonin
can inhibit reproductive function via testosterone-induced
LH suppression, while lower doses reinforce circadian activity,
possibly improving fertility.27
Anti-oxidant activity
The in vitro effects of melatonin are similar to those of
glutathione and tocopherol (Vitamin E) in scavenging
hydroxyl and neutralization of peroxyl radicals, thus reducing cellular damage from reactive oxygen species.20 28 29
This is fundamental to the ageing process. Anti-apoptotic
activity has also been described.30 A recent review of the
anti-oxidant properties of melatonin in brain tissue31
emphasized its role to limit free radical damage and potentially the development of neurodegenerative diseases, as
cerebral metabolism requires a high oxygen turnover and
oxidizable fatty acids.
Moreover, melatonin has shown to inhibit lipid peroxidation32 and slow the degenerative changes and clinical
progression of Alzheimer’s disease.33 Melatonin inhibits the
oxidation of dopamine34 in addition to similar protective
effects in other organs.35 36
574
Pro-oxidant activity
Although melatonin has anti-oxidant effects, it also shows
pro-oxidative properties. These oxidative effects are considered to be responsible for the anti-microbial properties of
melatonin.37 It has been shown that melatonin reduces
viraemia, delays the natural history of viral disease, and
reduces mortality in animal models.37 In addition, melatonin
inhibits the growth of mycobacterium tuberculosis in animal
models.38 Through the stimulation of interferon g, melatonin
halves intracellular load of chlamydial infection in a dosedependent effect.39 Chlamydial growth is also reduced by
the effect of melatonin modulating intracellular calcium and
cyclic AMP levels.40 Melatonin also exhibits anti-microbial
effects by reducing bacterial lipid content and by having ironbinding properties, leading to bacterial substrates depletion.41
Inhibition of neoplasic growth
Animal studies have demonstrated that melatonin delays the
progression of hormone-dependent cancers. Although the
precise mechanisms of cancer prevention by melatonin are
not clear, repression of pro-oncogenic genes22 and circadian
coupling optimizing immune cell function are suggested
effects.42 43
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Potential use of melatonin in sleep and delirium
Immune regulation
Dependent on the type and site of release, melatonin can
show a paracrine, autocrine, and intracrine action. It can
be peripherally released from leucocytes, mast cells, bone
marrow, and thymocites, displaying a wide range of immunomodulatory effects. These physiological effects include
the augmentation of CD4 cells, reduction of CD8 cells, cytokine regulation, T-cell signalling, and anti-inflammatory
effects by down-regulation of neuronal nitric oxide synthetase (Nos).22
Neuroprotection
Models of traumatic brain injury suggest that melatonin may
have neuroprotective effects mediated through the inhibition
of excitotoxic damage and by preventing ischaemia–reperfusion injury.44 Melatonin has also been shown to reduce body
temperature in humans,45 which has been associated with
improved neurological outcome after cardiac arrest, in
addition to improved regional cerebral blood flow, in animal
models.46
Sleep regulation
Although melatonin regulates sleep, the correlation between
levels of melatonin and the different sleep phases is
weak.47 – 49 In subjects with a free-running pattern of
release, melatonin induces sleep during its peak secretion
in daytime.50 51 After melatonin administration, a dosedependent shift in the timing of sleep occurs. Sleep benefits
associated with the use of melatonin are an increase in the
total sleep time (TST), sleep efficiency, and stage 2 sleep
with a reduction in slow wave sleep.14 In addition to the
effects on sleep phases, melatonin maintains synchronization in situations where the circadian rhythms are jeopardized and resynchronizes subjects after a period of free-run
release.
Melatonin in management of ICU-related
delirium
It is known that patients admitted to ICU develop impaired
sleep patterns.2 52 53 Typical findings include increased
latency and arousals, reduced TST54 with increased fragmentation, a higher proportion of stage 1 sleep (or light sleeping),
and reduced rapid eye movement (REM) sleep.55 Factors,
which contribute to sleep impairment in the ICU,52 56 57
include the use of opioids and benzodiazepines which
disrupt REM sleep,58 the impact of specific patient therapies
such as asynchrony to mechanical ventilation,59 arousal
related to patient care-related activities,60 environmental
noise,11 53 and non-phasic light exposure. Adverse effects
associated with sleep deprivation include impaired lung
mechanics,61 sympathetic –parasympathetic imbalance,62
cellular and humoral immunosuppression,63 64 impaired
endocrine responses,65 and significant psychological abnormalities such as inattention, impaired intellectual performance,66 and delirium.67
There are strong associations between sleep deprivation
and delirium in the elderly,68 – 72 postoperative patients,71 73
and the critically ill.52 56 57 However, such associations are
derived from cohort studies. It remains uncertain if sleep
deprivation is a cause of delirium or whether both represent
aspects of ‘ICU syndrome’ with apathetic delirium misinterpreted as a state of oversedation or sleep (Fig. 3). As delirium
is an independent predictor of death at 6 months and length
of hospital stay,74 the use of regular and formal assessment
using tools such as the Confusion Assessment Method scale
(CAM-ICU) in conjunction with Richmond agitation scale
(RASS)74 has been advocated to ensure an early diagnosis.
Given the relationship between sleep disturbance and
delirium, methods to improve sleep have been the focus of
several studies.13 75 – 81
During critical illness, there is abnormal release of melatonin and its plasma concentration and that of its urinary
metabolite are altered.13 75 – 77 81 Although lower levels of
melatonin and disrupted circadian release of melatonin
have been correlated with ICU delirium,13 causality has not
been established. Surgical stress reduces melatonin release
from the pineal gland,82 – 85 but this is confounded by the
effects of perioperative medications such as opioids. Finally,
with regard to the physiology of melatonin, it is still unclear
if the concentration of its metabolite is a true reflection of
its plasma concentration; also, if the excretion of melatonin
during critical illness is comparable to that during healthy
states.13 75 76
Despite suggesting a role of exogenous melatonin supplementation in patients suffering from lower plasma levels of
melatonin or an abnormal secretion pattern,48 86 there are
no studies successfully demonstrating that melatonin
administration in ICU leads to better sleep. However, there
are several limitations in these studies.
The method of sleep assessment
The length and quality of sleep have been the endpoints of
studies designed to assess melatonin efficacy. However,
heterogeneous methodologies relate to the definition and
analysis techniques of sleep (Table 1),48 86 87 and the use
of different endpoints may explain the varied results
(Table 2). Studies have used either subjective assessments,86
a sleep and activity log (actigraph),48 or a combination of bispectral index (BIS) and nursing assessments87 for the
analysis of sleep. While there are studies assessing the
quality of sleep in critically ill patients using the gold
standard technique of polysomnography,1 88 – 91 this has
not been used to assess the effects of melatonin.
Melatonin administration
A variety of doses and preparations of melatonin have been
used in the studies assessing the efficacy of melatonin to
improve sleep in critically ill patients (Table 3). Melatonin
can be given orally or i.v. and has a short half-life of 20–60
min. Pharmacokinetic studies using 3 mg of melatonin in
critically ill patients showed earlier peak concentrations,
575
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Bellapart and Boots
+
Impaired circadian rhythms
+
Drugs
+
B 1 down-regulation
Reduction Cortisol
Critical illness
Reduction Melatonin
Reduction of melatonin release
+
ICU environment
Light
Noise
Loss of Zeibgeibers
+
Insomnia
Prolonged ICU days
Prolonged ventilation days
Sleep deprivation
Delirium
Fig 3 Proposed pathophysiology of ICU delirium. The relationship between the ICU environment and the development of delirium shows an
altered release of melatonin and a fragmentation of biological and circadian rhythms.
Table 1 Endpoints and characteristics of the studies using melatonin in ICU. BIS, bispectral index; SEI, sleep efficiency index; SAS, sedationagitation-score. *Riker-SAS, sedation agitation scale
Study
Primary endpoint
Secondary endpoints
Delirium
Noise
conditions
Light conditions
Bourne and
colleagues87
Quality of sleep
assessed by BIS
defined by SEI
SEI measured by actigraph and nurse
assessment
Not assessed
Not measured,
not assessed
Optional use of
ear plugs
Not measured, not
assessed
Optional use of eye
masks
Ibrahim and
colleagues86
Number of hours of
observed sleep by
bedside nurse
Incidence of agitation assessed by
Riker-SAS* scale and required dose of
anti-psychotic medication or sedatives
Agitation
assessed by
Riker-SAS scale***
Delirium not
assessed
Not measured,
not assessed
Not measured, not
assessed
Shilo and
colleagues48
Sleep duration and
quality evaluated
using actigraphy
Not specified
Not assessed
Not measured,
not assessed
Bedside lights
reduced ,100 lux
from 22 h
plasma concentrations 10 times greater,92 and slower
plasma clearance compared with healthy subjects.93 The
prokinetic effects of continuous enteral feeding and in
particular lipophilic feeds increase melatonin absorption.92
Melatonin is metabolized in the liver with an extensive
first-pass effect. The main metabolite, MT6, is produced by
576
hydroxylation and sulphate conjugation, while a minor
metabolite is present as a glucuronide conjugate. Excretion
shows a biphasic pattern; however, individual patient
pharmacokinetics is extremely variable. Some authors have
reported better effects with doses ,0.5 mg than with
higher doses.87
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Potential use of melatonin in sleep and delirium
Table 2 Endpoints results after melatonin administration in ICU. AUC, area under the curve; BIS, bispectral index; SEI, sleep efficiency index;
*P¼NS, no statistically significant difference
Study
Primary endpoint
Results for primary endpoint
Secondary endpoints
Results for secondary
endpoints
Bourne and
colleagues87
Quality of sleep
assessed by BIS
defined by SEI
Nocturnal sleep time 3.5 h in the
melatonin group and 2.5 h in the
placebo group (P¼NS),* BIS—AUC
showed a statistical difference of 7%
decrease compared with the placebo
group, suggesting ‘better’ sleep
SEI measured by actigraph and
nurse assessment
Similar
Ibrahim and
colleagues86
Number of hours
of observed sleep
by bedside nurse
Patients under melatonin had 240
min median length of sleep; the
placebo group had 243.4 min median
length of sleep
Incidence of agitation assessed
by Riker-SAS scale and required
dose of anti-psychotic
medication or sedatives
The incidence of agitation was
31% in the melatonin group
compared with 7% in the
placebo group (P¼NS).
The requirements of extra
sedation or anti-psychotic
medication were similar in both
groups
Shilo and
colleagues48
Sleep duration and
quality evaluated
using actigraphy
Control group showed a TST of 7.4
(2.1) h compared with 6.3 (1.1) h
(P¼NS)
Not specified
Not specified
Table 3 Melatonin administration in ICU, overview of studies and characteristics. COAD, chronic obstructive airway disease
Study
Sample
size
Inclusion criteria
Exclusion criteria
Melatonin
dose
Time of
administration
Number of
treatment
nights
Quantity of
melatonin
administrations
Bourne and
colleagues87
24
patients
Acute respiratory
failure; ventilator
weaning;
tracheostomy
5 days of weaning;
sleep disorders;
intolerance to enteral
feeds; previous
convulsions, psychiatric
disorders, alcoholism,
or severe heart failure
10 mg
21 h
Four
consecutive
nights
Once per night.
Ibrahim and
colleagues86
32
patients
Tracheostomy;
ventilator; weaning;
GCS .9; off sedation
for .12 h
Age ,16 yr; pregnancy
or breastfeeding;
intolerance to enteral
feeding; expected
death within 24 h
3 mg
22 h
Minimum of
three nights
and until ICU
discharge
Once per night
Shilo and
colleagues48
8
patients
Stable
haemodynamics;
COAD; ventilator;
weaning
Patients requiring
narcotics or sedatives
3 mg slow
released
22 h
Three
consecutive
nights
Once per night
Although the sleep effects of melatonin have been
described when used in the general population with a wide
range of doses,94 – 97 the optimal dose of melatonin has not
been determined for use in the critically ill.
bedside. The other studies either did not control light
intensity86 or were confounded by a variable light exposure
due to eye masks being offered at individual patient
discretion.87
Melatonin administration and environmental light
There is no uniformity for the control of patient exposure to
light among the studies using melatonin in ICU. In a study
where light was limited to ,100 lux,48 the light was
only reduced from 22:00 h and measurement took place
in the general unit rather than at the patient’s
Melatonin administration and environmental noise
Only one study has attempted to control environmental
noise. Ear plugs were offered but not mandated for patient
use.87 This inconsistency in the control on environmental
noise confounds any conclusion.
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Melatonin and patient characteristics
Casemix variations, illness severity, and concurrent medications vary between studies. In one study, 24 patients were
recruited when they were in the weaning phase from mechanical ventilation and if they had a tracheostomy.87 However,
patients were excluded if the length of stay in ICU was ,5
days or if they had a history of sleep apnoea, previously diagnosed sleep abnormalities, psychiatric disorders, alcoholism,
and failure to maintain enteral feeding, low levels of
consciousness, or severe heart failure. Propofol, morphine,
and midazolam were stopped for least 48 h before study
entry. In another study, 32 patients with a tracheostomy
during ventilation wean were recruited excluding those
patients ,16 yr of age, who were pregnant or not enterally
fed. The period allowed for clearance of previous sedation
was unclear. The casemix included patients with severe
sepsis and those taking corticosteroids or b-blockers, conditions known to depress melatonin secretion.86 In a study of
eight patients, only four were on mechanical ventilation,
and were excluded if they were haemodynamically unstable
or receiving narcotics and benzodiazepines.48
The efficacy of melatonin for the prevention of delirium
has been studied in other populations. Elderly patients
admitted to medical wards were randomized to receive
either placebo or physiological doses of melatonin (0.5 mg
nocte).98 The study showed a significant reduction in the incidence of delirium (as measured by the CAM scale) in the
interventional group when compared with the control
group. This is the first study to show a direct effect of melatonin on delirium.
In conclusion, sleep disruption and delirium are recognized as significant management complications in the ICU
and they are associated with abnormal release of melatonin.
Although of potential, the use of melatonin to treat ICU
delirium and sleep disruption is confounded by limited
studies and varied methodology. Therefore, recommendations regarding the use of melatonin to prevent critically ill
delirium cannot be made at this time. Further randomized
control studies using more physiological doses of melatonin
and controlling environmental variables such as light and
noise are required.
Declaration of interest
None declared.
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