Delirium and sleep quality in the intensive care unit: the role of melatonin

Full text

Critical Care Science
https://doi.org/10.62675/2965-2774.20240083-en
Crit Care Sci. 2024;36:e20240083en
Delirium and sleep quality in the intensive care unit: the role of melatonin
Pedro Henrique Rigotti Soares1, Rodrigo Bernardo Serafim2,3
1 Intensive Care Unit, Hospital Nossa Senhora da Conceição, Grupo Hospital Conceição - Porto Alegre (RS), Brazil.
2 Instituto D’Or de Ensino e Pesquisa - Rio de Janeiro (RJ), Brazil.
3 Department of Internal Medicine, Universidade Federal do Rio de Janeiro - Rio de Janeiro (RJ), Brazil.
CORRELATION BETWEEN
DELIRIUM
AND SLEEP DISORDERS
Patients in intensive care units (ICUs) frequently face challenges related to delirium and sleep disturbances.(1) Despite
extensive research in recent years, delirium remains a complex condition with uncertain pathophysiology, and its occurrence
is associated with worse outcomes as well as longer durations cognitive and functional impairment.
(1,2)
Although no study
has shown a strong relationship between ICU delirium and sleep to date, the development of delirium and sleep disturbance
in the ICU is often multifactorial, with numerous related risk factors, including age, comorbidities, disease severity,
environmental factors, and iatrogenic interventions.(3)
e lack of evidence supporting the use of pharmacological interventions (such as antipsychotics or sedatives) for delirium
prevention or treatment in the ICU(4) highlights the importance of targeted interventions to mitigate the risk of delirium
and its predisposing conditions.
(3,4)
Current recommendations for delirium prevention emphasize nonpharmacological
measures, such as optimizing human care (eCASH),(5) the well-established A to F bundle,(6) and eorts to minimize
modiable risk factors. e PADIS guidelines maintain that sleep should be routinely monitored, and strategies for sleep
hygiene enhancement should be discussed with patients.
(7)
Despite these eorts, sleep disturbances, such as sleep deprivation,
are still reported by 66% of ICU patients
(8)
and are linked to neurocognitive dysfunction, which further increases the risk
of delirium.(9)
SLEEP QUALITY IN THE INTENSIVE CARE UNIT
Sleep in the ICU has been shown to be characterized by subjectively poor quality, high levels of fragmented sleep, and
prolonged sleep latencies. Moreover, nearly 50% ofICU sleepoccurs during the daytime, thus impacting rehabilitation.
Although sleep is considered crucial for patient recovery, little is known about the association of sleep with physiologic
function among critically ill patients or those with clinically essential outcomes in the ICU. Research involving ICU-based
sleep disturbance is challenging due to the lack of objective, practical, reliable, and scalable methods to measure sleep
and the multifactorial etiologies of its disruption.
(10,11)
Electroencephalography studies have described frequent arousal,
an increase in stage 2 non-REM sleep, a reduction or absence of slow-wave stage 3 non-REM sleep, and REM sleep.(10)
e poor quality of sleep in the ICU can be attributed to articial light, increased noise, a consequence of critical illness,
and treatment interventions that aect the day‒night cycle.
(10)
Given the challenges of improving sleep via workow and
environment redesign, pharmacological therapies with traditional sleeping pills, such as benzodiazepines, have been largely
used, thus increasing the risk of developing delirium. Even newer nonbenzodiazepine hypnotics, such as zolpidem or atypical
antipsychotics (not approved by the Food and Drug Administration for this purpose), are associated with altered mental
status and in-hospital falls and may lack ecacy even in less acutely ill patients.(11)
THE ROLE OF MELATONIN IN THE INTENSIVE CARE UNIT
Melatonin, a hormone produced by the pineal gland, plays a pivotal role in regulating the sleep-wake cycle.
Environmental cues, especially light exposure, inuence its secretion, with peak levels typically occurring at night. In the
This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
EDITORIAL

2Soares PH, Serafim RB
Crit Care Sci. 2024;36:e20240083en
ICU, patients are often exposed to articial lighting and
noise, disrupting their circadian rhythm and melatonin
production.
(10)
e evidence of decient melatonin levels
in critically ill patients makes it theoretically reasonable
to expect more signicant eects of melatonin to enhance
sleep quality and consequently reduce delirium incidence
in ICU settings.(12)
However, despite the promising results of melatonin
in improving sleep quality(3) and preventing delirium
in non-ICU settings,(13) the efficacy of melatonin or
ramelteon (a melatonin agonist) in preventing delirium
in the ICU remains a topic of debate, with conicting
ndings reported in recent studies. Two recently published
systematic reviews and meta-analyses showed discordant
results and highlighted several methodological limitations,
such as the relatively low number of patients selected,
heterogeneity of melatonin doses, and the use of dierent
delirium assessment tools.(3,13)
Bandyopadhyay et al. conducted a randomized
controlled trial with a 7-day follow-up to compare
standard care alone or in combination with 3mg of
enteral melatonin once a day. e trial was conducted in
a tertiary ICU in India on patients with a clinical-surgical
prole. e study involved a total of 108 patients, and
measurements of the incidence of delirium were carried
out on days 1, 3, and 7 of hospitalization in the ICU. e
aim of using melatonin was to reduce episodes of delirium
in patients. Although the study was well conducted with
quality randomization and standardization of outcome
assessment methods, it did not demonstrate any benet
of using melatonin to reduce the incidence of delirium by
optimizing the sleep-wake cycle. e results of this trial add
to others who did not demonstrate the benet of using this
medication as prophylaxis and/or treatment for patients
with delirium. e author discussed delirium as a complex
multifactorial disorder with underlying mechanisms
and stated that addressing only one such mechanism
(disruption of the circadian rhythm) may not be enough
to determine the eect size initially aimed for in this study.
However, the study did not use any method to measure the
quality of sleep of patients in each group.(14)
BEDSIDE STRATEGIES FOR
DELIRIUM
AND SLEEP
MANAGEMENT
Nonpharmacological therapies are the cornerstone for
promoting sleep quality and preventing delirium in the
ICU. Strategies for improving sleep hygiene should be
implemented in the ICU environment, including reducing
noise (not exceeding 40 dB), adjusting syringe pump
alarms, ensuring adequate light levels, avoiding procedures
during nighttime, reviewing all current medication and the
possibility of withdrawal (including nicotine or recreational
addictive substances), optimizing ventilator settings, and
even implementing alternative therapies for sleep promotion,
including music, massage, or relaxation techniques.(9)
Given the multifactorial nature of these conditions, a
holistic approach encompassing both pharmacological and
nonpharmacological interventions is essential.
Despite the controversy regarding the use of melatonin in
enhancing sleep quality and potentially reducing the incidence
of delirium, further research is needed to clarify its ecacy
and optimal dosing strategies in the ICU setting. Additionally,
addressing other contributing factors beyond circadian
rhythm disruption may be necessary to achieve meaningful
improvements in delirium prevention and management.
Publisher’s note
Conflicts of interest: None.
Submitted on March 9, 2024
Accepted on March 14, 2024
Corresponding author:
Rodrigo Bernardo Serafim
Departamento de Medicina Interna
Universidade Federal do Rio de Janeiro
Avenida Carlos Chagas Filho, 373
Zip code: 21044-020 - Rio de Janeiro (RJ), Brasil
E-mail: rodrigobserafim@gmail.com
REFERENCES
1. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and
consequences of ICU delirium. Intensive Care Med. 2007;33(1):66-73.
2. Rego LL, Salluh JI, Souza-Dantas VC, Silva JR, Póvoa P, Serafim RB.
Delirium severity and outcomes of critically ill COVID-19 patients. Crit Care
Sci. 2023;35(4):394-401.
3. Gandolfi JV, Di Bernardo AP, Chanes DA, Martin DF, Joles VB, Amendola
CP, et al. The effects of melatonin supplementation on sleep quality
and assessment of the serum melatonin in ICU patients: a randomized
controlled trial. Crit Care Med. 2020;48(12):e1286-93.
4. Barbateskovic M, Krauss SR, Collet MO, Larsen LK, Jakobsen JC, Perner
A, et al. Pharmacological interventions for prevention and management of
delirium in intensive care patients: a systematic overview of reviews and
meta-analyses. BMJ Open. 2019;9(2):e024562.
5. Vincent JL, Shehabi Y, Walsh TS, Pandharipande PP, Ball JA, Spronk P, et
al. Comfort and patient-centered care without excessive sedation: the
eCASH concept. Intensive Care Med. 2016;42(6):962-71.
6. Morandi A, Brummel NE, Ely EW. Sedation, delirium, and mechanical
ventilation: the “ABCDE” approach. Curr Opin Crit Care. 2011;17(1):43-9.
7. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJ, Pandharipande
PP, et al. Clinical Practice Guidelines for the Prevention and Management
of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in
Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-73.

Delirium and sleep quality in the intensive care unit 3
Crit Care Sci. 2024;36:e20240083en
8. Shih CY, Wang AY, Chang KM, Yang CC, Tsai YC, Fan CC, et al. Dynamic
prevalence of sleep disturbance among critically ill patients in intensive
care units and after hospitalization: a systematic review and meta-analysis.
Intensive Crit Care Nurs. 2023;75:103349.
9. Dorsch JJ, Martin JL, Malhotra A, Owens RL, Kamdar BB. Sleep in the
intensive care unit: strategies for improvement. Semin Respir Crit Care
Med. 2019;40(5):614-28.
10. Tiruvoipati R, Mulder J, Haji K. Improving sleep in intensive care unit: an overview
of diagnostic and therapeutic options. J Patient Exp. 2020;7(5):697-702.
11. Owens RL. Better sleep in the intensive care unit: blue pill or red pill or no
pill? Anesthesiology. 2016;125(5):835-7.
12. Yan W, Li C, Song X, Zhou W, Chen Z. Prophylactic melatonin for delirium
in critically ill patients: a systematic review and meta-analysis with trial
sequential analysis. Medicine (Baltimore). 2022;101(43):e31411.
13. Aiello G, Cuocina M, La Via L, Messina S, Attaguile GA, Cantarella G, et al.
Melatonin or ramelteon for delirium prevention in the intensive care unit:
a systematic review and meta-analysis of randomized controlled trials. J
Clin Med. 2023;12(2):435.
14. Bandyopadhyay A, Yaddanapudi LN, Saini V, Sahni N, Grover S,
Puri S, et al. Efficacy of melatonin in decreasing the incidence of
delirium in critically ill adults: a randomized controlled trial Crit Care Sci.
2024;36:20240144en.