Consistent with previous studies in other samples [6,10,31], we found that nocturnal sleep and body production of melatonin are both disturbed in healthy subjects exposed to simulated ICU noise and light, suggesting our protocol was suitable to test our hypotheses. More importantly, we noted that use of both oral melatonin, and earplugs and eye masks improve sleep quality at different levels, especially melatonin.

In the first part of the study, our results confirmed that in simulated ICU noise and light, healthy subjects not only had greater anxiety and poorer subjective sleep quality, but also suffered from the disturbance of sleep structure, measured as shorter total sleep time, longer sleep-onset latency, longer REM latency, more light sleep, less REM sleep and more arousals and awakenings. Although previous studies have suggested that ICU noise disturbs the sleep quality of healthy subjects to varying degrees [10,31], only the research reported by Hu et al. was similar to ours, which combined levels of noise and light in a simulated ICU environment in a sleep laboratory [6].

Although the ICU environment might not be responsible for the majority of ICU sleep disturbance, excessive noise and long-lasting light have proved to be the important and inevitable factors and have negative physiological and psychological effects on patients [9,34]. In some ICUs, a single-bedded room has been chosen for noise reduction, however, most noise leaks from the main ICU [9]. Although mean sound and mean maximum sound intensities are significantly reduced in a single-bedded room, the frequency of sound spikes remained elevated so there is still a lack of improvement in sleep continuity. Recent emphasis has been on controlling noise level and encouraging the dimming of lights overnight in ICU settings, but control of noise is not always possible, and lights are always present in critical care for patient observations and patient care activities [12]. Therefore, some domestic and international experts recommend that the ICU incorporates earplugs/eye mask into routine nursing care [13]. In the second part of our study, consistent with previous studies, use of earplugs and eye masks significantly improved the sleep quality, as seen in shorter sleep-onset latency, reduced number of arousals and awakenings, better perceived sleep quality and less anxiety. But the tolerability of this intervention is critical. Previous studies showed that some ICU patents were unwilling to use the earplugs and/or eye masks because they found the intervention uncomfortable [28]. In our study, most subjects who wore earplugs and eye masks considered this strategy was effective, however, the discomfort of earplugs is a big problem. Some patients commented that there a feeling of tightness, sore ears, claustrophobia and still being able to hear when using earplugs. So it is necessary to explore other methods that are better tolerated and even more effective.

An ideal sleep-improvement strategy for avoiding disruption of the ICU environment should be economical, feasible, rapid in onset and offset, and without local or systemic adverse effects. Recently, melatonin has raised concerns among ICU experts. Melatonin is a key circadian regulatory neurohormone mainly secreted by the pineal gland. Light signals play the most important role in the synthesis and secretion of melatonin in the organism via the retina and retina-hypothalamic pathways, acting directly on the suprachiasmatic nuclei (SCN). So melatonin secretion normally increases at night and decreases in the early morning hours. The melatonin rhythm functions to synchronize circadian rhythms, whereas the melatonin rhythm along with all other circadian rhythms are synchronized by the central pacemaker. Therefore, melatonin is a good sleep aid. The interest in melatonin as a potential therapeutic or prophylactic agent in management of sleep disturbance in the ICU derives from demonstrated low plasma concentrations and altered secretion patterns of melatonin in the critically ill patients [23,24,27]. However, the physiological regulation of melatonin secretion by darkness and light is abolished in severely ill patients in ICU [14], so use of eye masks or dimming the lights only might be not enough to return to normal levels. Thus, supplementation of exogenous melatonin, to remodel the melatonin level in the human body that approaches the physiological state, might be a potential strategy for improving sleep among ICU patients.

The second part of our study investigated and compared the effect of oral melatonin and use of earplugs and eye masks on sleep quality and serum melatonin level in a simulated ICU noise and light environment. Both earplugs and eye masks, and oral melatonin, significantly improved sleep quality, in addition to shorter sleep-onset latency and reduced number of arousals and awakenings; melatonin also increased the duration of REM sleep stage and total sleep time. Furthermore, when oral melatonin was compared to wearing earplugs and eye masks, there was a significant decrease in awakenings and arousals during simulated ICU noise and light. The encouraging results were established both by PSG and by participants’ self-reports and showed that sleep in the simulated ICU noise and light environment while wearing earplugs and eye masks, or after taking melatonin, was more restorative and less fragmented. Although there is no consensus on the relative functions of the various sleep stages, REM sleep generally is considered to be important for cognitive restoration [35]. On the other hand, both awakenings and arousals, and acoustic events, can accelerate the heart rate, which is linked to adverse cardiovascular events and may impair the patient’s recuperation [36-38]. Compared to earplugs and eye masks, melatonin administration might benefit sleep better by three mechanisms: (1) although earplugs can lower noise at a certain degree, the frequency of sound spikes remained elevated, which is an important contributor to noise-induced sleep disruption. However, melatonin has some degree of sedative effect [39] and might buffer the stress from noise. That is probably why in our study melatonin administration without any intervention for attenuating ambient noise improved sleep under the noisy overnight sleep conditions; (2) some patients considered the discomfort of earplugs and eye masks to affect sleep quality; (3) wearing earplugs and eye masks could not make the declined melatonin level return to the normal level, but melatonin supplements could bring a them to a higher level.

Although the cause of the low melatonin level in ICU patients is still unclear, ICU noise and illumination should be significant factors. In the study of Hu et al. simulated nocturnal ICU noise and light caused low urinary secretion levels of 6-sulphatoxymelatonin (6-SMT) and high urinary cortisol during the night, and earplugs and eye masks elevated the nocturnal levels of 6-SMT, which suggests that raising the melatonin level might be one of the mechanisms for improving sleep quality [6]. However, metabolites of melatonin cannot entirely represent the true level in the body [40].

There has been no study on the impact of ICU noise and light on nocturnal serum melatonin levels. In normal physiological conditions, the melatonin peaks between 02:00 and 04:00, and troughs during daytime. The average peak melatonin concentration at night is 60 pg/mL, which gradually declines to trough levels of 10 pg/mL during the daytime [15]. Our results for the baseline night were similar to those values. In our study, ICU noise and light significantly suppressed the melatonin level and delayed the peak of melatonin, which also fits with the retrospective study by Jamie et al., who found that even small changes in ordinary light exposure during the evening can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker [41]. We also found that although the subjects were exposed to light overnight, the nocturnal melatonin level still maintained a certain rhythm. Some investigators have speculated that the regulation of melatonin secretion by direct control by the environmental light-dark cycle has conferred on humans an evolutionary advantage [42].

In our study, we found that administration of 1 mg of fast-release melatonin was successful in achieving good absorption. The mean maximal serum melatonin concentration was reached at about 1 h after administration, which was close to 20 times higher than the NL-night levels and 12 times higher than baseline levels, and then the levels fell but still remained at a higher level than on the NL, NLP and NLEE nights. Although oral melatonin might result in 10 to 100 times the normal peak night-concentration after ingestion, it has a wide safety margin [29]. It is theoretically possible that high levels of melatonin were achieved with a high dose at night, so that even during the daytime, melatonin blood levels were sufficiently high to promote diurnal sleep as well [29]. Daytime sleep would have then occurred and made nocturnal sleep more difficult. In addition, controlled release formulations would bring an increased risk of prolonged periods of supraphysiologic melatonin levels [43], therefore, we chose a relatively low dose of fast-released melatonin for our study. However, after melatonin administration the melatonin levels were lower than those in previous studies, perhaps because of overnight illumination exposure. The most suitable dose of melatonin in critically ill patients in ICU should be confirmed further, because Mistraletti et al. found that after administration of indole the melatonin peak was reached earlier in ICU patients than in healthy volunteers, and the rate of melatonin disappearance was slightly slower [44]. In our study, using earplugs and eye masks during the simulated ICU noise and light elevated melatonin level to some degree and advanced the timing of the clock. However, the melatonin level was much lower than in the melatonin group and that is one of the reasons why melatonin has greater benefit on sleep in the simulated ICU environment.

Our study design has some limitations, which should be reviewed. First, the study was performed in a sleep laboratory with healthy subjects rather than in an ICU setting of critically ill patients, and therefore could not completely simulate the full auditory and visual experience of the ICU. Second, the study was only performed for a 9-h nocturnal period rather than over 24 h. The ICU patients experience circadian rhythm disturbances with sleep traversing the day and night. Therefore, an ideal study should measure the sleep in healthy volunteers lying recumbent over a 24-h period to completely simulate the ICU scenario. In addition, our sample sizes were small, which limited the power of our statistical analyses. Future studies with larger numbers and greater diversity of participants would likely support these recommendations. Finally, although no adverse effects related to the oral melatonin were observed in our healthy subjects during the study period, the potential safety issues related to melatonin administration in ICU patients need to be considered, and the impact of oral melatonin on critically ill patients with ICU sleep deprivation will be our next study focus.