Sleep deprivation is a major concern in critically ill patients in intensive care units (ICU). Several studies have shown that poor sleep quality and the inability to sleep are the second largest stressors and rank among the top three major sources of anxiety during ICU stays
[1–3]. Sleep for ICU patients is characterised by frequent disruptions, loss of circadian rhythms and a paucity of time spent in restorative sleep stages. Typical findings described by polysomnography (PSG), the gold standard of assessing sleep quality, include increased latency, a higher proportion of non-rapid eye movement (NREM) sleep stage 1 and 2 (or light sleep), and reduced restorative slow wave (SW) and rapid eye movement (REM) sleep, largely because of frequent waking. Although ICU patients may experience normal or near normal total sleep time (TST), approximately 50% of this sleep occurs during the daytime
[4, 5]. In a recent observational study by Elliot et al. a 24-hour PSG was used to evaluate the sleep quality in ICU patients
. They found that despite improvements in ICU design, technology and healthcare personnel training, there has been no improvement in the ICU sleep problem
[5–7]. It has been found that there are many extrinsic and intrinsic factors of sleep deprivation in the ICU setting including noise, light, nursing procedures, the presence of existing diseases, inflammatory mediators, anxiety, pain, sedative and opioid medications and mechanical ventilator setting
[8–12]. Furthermore, the occurrence of ICU sleep deprivation is associated with detrimental outcomes, including delirium, difficulty weaning, increased nosocomial infections, prolonged ICU length of stay (LOS) and increased ICU mortality
Conversely, despite the poor sleep quality that disturbs almost all ICU patients, clinicians remain reluctant to administer traditional sedative-hypnotic drugs in patients with sleep disorders. The major concerns are the side effects of these drugs, mainly that they destroy the structure of sleep, reduce the clinician’s ability to monitor the level of consciousness, induce respiratory depression and lower blood pressure
Sleep goals for ICU patients are to get enough sleep, reset the disordered circadian rhythms, adjust the abnormal sleep structure, reduce sleep interruption, overcome fatigue and anxiety, facilitate nursing care and treat disease. An ideal therapy for improving sleep in the ICU should be economical, feasible, rapid in onset and offset and without local and systemic adverse effects. At present, there is no effective treatment in use to improve ICU sleep that covers all of these ideal properties. Current studies are mainly focused on non-drug treatments such as earplugs and/or eye masks
[10, 15] and imagery and relaxation
. These treatments are relatively safe but do not guarantee efficacy. Among the studies, the clinical research on earplugs and/or eye masks has some maturity
. Some domestic and international experts and scholars have recommended that ICUs incorporate earplugs and/or eye masks into routine nursing care
. However, Bourne et al.
 and Gabor et al.
 showed that environmental factors were responsible for a fraction of arousals and awakenings, and Perras et al.
 indicated that the physiological regulation of melatonin secretion by darkness and light was abolished in severely ill patients in the ICU. Therefore, treatments based on environmental factors might have limited effects. Recently melatonin, a physiological sleep aid, has gained interest among ICU scholars.
Melatonin (N-acetyl-methoxytryptamine) is a neurohormone mainly secreted by the pineal gland. Light signals play the most important role in the synthesis and secretion of melatonin in organisms. Thus, the environmental cues that regulate an organism’s biological clock are predominantly the daily alternation of light and darkness acting via the retina and retina-hypothalamic pathways directly on the suprachiasmatic nuclei (SCN). Melatonin secretion increases directly with the length of darkness. Increased light intensity decreases the quantity of endogenous melatonin produced and shifts the pattern of release throughout the circadian clock. Endogenous melatonin is released at night, beginning at approximately 9:00 pm with a peak release at between 2:00 and 4:00. Melatonin release is typically inhibited between 7:00 and 9:00, coinciding with the peak of endogenous cortisol
. This secretion pattern makes the physiological activities in the human body, such as the sleep-wake cycle, synchronised with the circadian rhythm. Thus, melatonin is a good sleep aid. In addition, current in vitro and in vivo experiments suggest that melatonin might act as a mood stabilizer, relieve stress, act as an anti-oxidation and anti-inflammation agent, suppress pathogens and protect the functioning of multiple organs
, which are undoubtedly helpful to the recovery of ICU patients, and thereby might improve sleep.
Prolonged-release melatonin (Circadin), an oral medication to regulate physiological sleep and the circadian rhythm designed to mimic the endogenous pattern of melatonin production, is licensed for the treatment of primary insomnia in patients aged 55 years and over. It results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life, without withdrawal symptoms upon discontinuation
. Recently, extensive clinical trials also noted that melatonin could be beneficial in different populations with sleep disorders. Firstly, melatonin might be effective for insomnia and daytime sleepiness caused by time zone changes
 and work shifts
 that induce the malfunctioning of biological clocks. This is because melatonin may maintain the synchronisation in situations where the circadian rhythms are jeopardized and resynchronize after a period of free-run release. Secondly, melatonin might improve the sleep quality of non-ICU critically ill patients with dialysis
, moderate to severe COPD
 and asthma
. In addition, the available clinical data shows that perioperative use of melatonin is effective in reducing preoperative anxiety
 and plays a role in the prevention of postoperative delirium
, as well as possessing certain analgesic qualities, and may reduce concomitant opioid use in the postoperative period with a corresponding reduction in opioid-associated side effects
Melatonin has been given safely to humans in doses of 1 to 15 mg. Although treatment results in plasma levels up to 100 times the normal peak night concentration approximately 1 hour after ingestion, it has a wide safety margin
. In a meta-analysis, Buscemi et al. concluded that melatonin is safe for short-term use
. They found that the most common side effects of melatonin use were headache, dizziness, nausea and drowsiness
. Most importantly, although melatonin has hypnotic, sedative and analgesic properties, it has few respiratory and hemodynamic effects.
The interest in melatonin as a potential therapeutic or prophylactic agent in the management of sleep disturbance in the ICU derives from the demonstrated low plasma concentrations and altered secretion patterns of melatonin in critically ill patients. Shilo et al. studied the day secretions of melatonin in a group of ICU patients compared to a group of patients in ordinary medical wards. They found that the nocturnal peak of melatonin was missing in most ICU patients
. Mundigler et al. described a disturbed pattern of circadian secretion of melatonin in ICU patients with sepsis (16 out of 17 patients) but a preserved circadian rhythm in ICU patients who did not have sepsis (six out of seven patients)
. Olofsson et al. found that the circadian rhythm of melatonin secretion was abolished in mechanically ventilated patients in the ICU
. Perras et al. suggested that the nocturnal melatonin concentrations in ICU patients were negatively correlated with illness severity
. In addition, various drugs commonly used in the ICU have been reported to alter melatonin secretion and to decrease the plasma levels of melatonin
 including benzodiazepines, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and beta-blockers. Therefore, low melatonin levels, poor sleep quality and illness have a reciprocal causation interaction and form a vicious circle. The supplementation of exogenous melatonin to remodel the melatonin level in the human body that approaches the physiological state might be one of most effective strategies for improving sleep.
Both melatonin and cortisol are biological markers of the circadian rhythm. Some previous studies have shown that there is a hypo-secretion of melatonin and an overall high cortisol excretion in most patients in the ICU. Cortisol is an important stress hormone that would be invoked by the noise, light and other stressors in the ICU and leads to anxiety and sleep disturbance. It is known that melatonin can reduce the adrenocortical response to stress and down-regulate the synthesis and release of cortisol. Moreover, in addition to reducing the stress, the role of melatonin as an antioxidant and anti-inflammatory agent or part of sepsis treatment is widely discussed. Thus, administration of melatonin might significantly benefit ICU patients.
Recently, Mistraletti et al. studied the pharmacokinetics of melatonin given orally to ICU patients and found a good oral bioavailability of the drug
. Additionally, several studies suggest it can take up to three days to achieve the desired effect of melatonin on sleep quality
[13, 18, 30, 37]. Until now, there have been only three studies investigating the influence of melatonin treatment on sleep quality in critically ill patients. Shilo et al.
 and Bourne et al.
 found that melatonin improved sleep quality and sleep length in critically ill patients in the ICU, however Ibrahim et al.
 found a negative result in their study. There are some inconsistencies regarding the inclusion criteria, the drug included, the sound and light control and the monitoring method in these three studies, specifically as follows:(1) Ibrahim et al.’s study included patients who had unlimited use of sedatives and analgesics that might affect serum melatonin levels; (2) there was no uniformity for the control of patient exposure to noise and light among the three studies, which may have a more powerful effect on observed sleep than even the pharmacological levels of melatonin achieved; and, most significantly, (3) they did not use the PSG (the gold standard for assessing sleep) to evaluate sleep quality and ignored the importance of monitoring the all-day sleep, likely because it is very difficult to perform 24-hour PSG in severely ill patients in the ICU.
The aim of the present work is to evaluate the efficacy and safety of melatonin for ICU sleep deprivation. Our hypothesis is that melatonin will improve the sleep quality in ICU patients. The present article proposes a protocol for a clinical study consisting of a double-blind, randomized, placebo-controlled trial with melatonin in adult critically ill patients with ICU sleep deprivation. The present report will follow the guidelines expressed by the Consolidated Standards of Reporting Trials (CONSORT).