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Patients in the intensive care unit often suffer from lack of sleep at night. We hypothesised that nocturnal melatonin may increase observed nocturnal sleep in tracheostomised patients.
Double-blind, randomised, placebo-controlled pilot study.
ICU of a tertiary hospital.
Thirty-two ICU patients with tracheostomy who were not receiving continuous se...
Citations
... The sleep observation tool (SOT) requires an observer to assess and document the patient's sleep or wake status every 15 min and has been found to correctly identify sleep 81.9% of the time compared to polysomnography. It has been used in its standard format to assess the effect of therapeutic interventions and in an amended format that uses 30-min intervals [156][157][158]. ...
... Because of the disturbed secretion of melatonin (described above), there is a biologically plausible rationale to support the use of exogenous melatonin. However, a meta-analysis of four studies reported that melatonin, at doses of between 3 and 10 mg per day, had uncertain effects on objective and subjective measures of sleep quantity and quality (Table 5) [136,158,[221][222][223]. ...
Sleep is a complex process influenced by biological and environmental factors. Disturbances of sleep quantity and quality occur frequently in the critically ill and remain prevalent in survivors for at least 12 mo. Sleep disturbances are associated with adverse outcomes across multiple organ systems but are most strongly linked to delirium and cognitive impairment. This review will outline the predis-posing and precipitating factors for sleep disturbance, categorised into patient, environmental and treatment-related factors. The objective and subjective methodologies used to quantify sleep during critical illness will be reviewed. While polysomnography remains the gold-standard, its use in the critical care setting still presents many barriers. Other methodologies are needed to better understand the pathophysiology, epidemiology and treatment of sleep disturbance in this population. Subjective outcome measures, including the Richards-Campbell Sleep Questionnaire, are still required for trials involving a greater number of patients and provide valuable insight into patients' experiences of disturbed sleep. Finally, sleep optimisation strategies are reviewed, including intervention bundles, ambient noise and light reduction, quiet time, and the use of ear plugs and eye masks. While drugs to improve sleep are frequently prescribed to patients in the ICU, evidence supporting their effectiveness is lacking.
... Expert consensus reports also support such a role of melatonin in adult insomnia (Wilson et al. 2010;Geoffroy et al. 2019;Palagini et al. 2020;Vecchierini et al. 2020). Melatonin reduces the need for sedation in ICU patients (Ibrahim et al. 2006;Bourne et al. 2008;Bellapart and Boots 2012;Mistraletti et al. 2015;Foreman et al. 2015;Soltani et al. 2020). Brusco et al. (2021) employed a 9 mg melatonin dose to improve clinical conditions and hastened recovery in a group of 37 hospitalized patients with COVID-19 pneumonia. ...
The COVID-19 pandemic posed a significant challenge to the global organization of health systems. The reallocation and concentration of available resources on the management of COVID-19 had a significant impact on all other health conditions due to the suspension or cancellation of screening and routine examinations, the reduction of referrals, and the redistribution of staff. The management of central disorders of hypersomnolence was also negatively affected, although some evidence has debated the role of the pandemic, which may have represented not only a challenge but also an opportunity for people with central disorders of hypersomnolence. On the one hand, the loss of zeitgebers as a result of changes in patients’ routines during the lockdown period, such as working from home, spending extended periods indoors, and a reduction in social interactions, could have worsened the management of these disorders. On the other hand, prolonged home confinement during the pandemic may have afforded more opportunities to implement the recommended behavioral strategies for reducing excessive daytime sleepiness and maintaining a more flexible sleep schedule. Consequently, the purpose of this chapter is to describe the most significant findings from studies examining the impact of the COVID-19 pandemic on central sleep disorders, with a particular emphasis on narcolepsy.KeywordsCOVID-19Central disorders of HypersomnolenceNarcolepsySleep MedicineExcessive daytime sleepiness
... Expert consensus reports also support such a role of melatonin in adult insomnia (Wilson et al. 2010;Geoffroy et al. 2019;Palagini et al. 2020;Vecchierini et al. 2020). Melatonin reduces the need for sedation in ICU patients (Ibrahim et al. 2006;Bourne et al. 2008;Bellapart and Boots 2012;Mistraletti et al. 2015;Foreman et al. 2015;Soltani et al. 2020). Brusco et al. (2021) employed a 9 mg melatonin dose to improve clinical conditions and hastened recovery in a group of 37 hospitalized patients with COVID-19 pneumonia. ...
Melatonin has been recognized for its therapeutic potential as a chronobiotic cytoprotective drug to combat the effects of COVID-19 infection. Melatonin may be unique in mitigating the symptoms of SARS-CoV-2 infection due to its wide-ranging actions as an antioxidant, anti-inflammatory, and immunomodulatory chemical. Furthermore, melatonin is an efficient chronobiotic drug in treating delirium and reversing the circadian disturbance caused by social isolation. Melatonin is a cytoprotector that helps to treat various comorbidities, including diabetes, metabolic syndrome, and ischemic and nonischemic cardiovascular disease, all of which increase COVID-19 illness. As the COVID-19 pandemic continues, it has become known that clinical sequelae and symptoms for a considerable number of patients may linger for weeks to months beyond the acute stage of SARS-CoV-2 infection (long COVID). Based on indications of neurological sequelae in COVID-19-infected individuals, there is another possible use of melatonin based on its documented neuroprotective properties. Melatonin is an excellent agent for controlling cognitive deterioration (brain fog) and pain in myalgic encephalomyelitis (i.e., chronic fatigue syndrome); therefore, its therapeutic importance for the neurological consequences of SARS-CoV-2 infection should be investigated.KeywordsCytokine stormCOVID-19Long COVIDViral infectionCoronavirusSepsis
... The idea to use melatonin in critically ill patients is based on the greater risk of development of delirium in this population of patients due to the greater severity of their clinical conditions and the characteristics of the ICU in terms of the noisy environment and alteration of the day-night cycle [32][33][34]. There is evidence of very low melatonin levels in critically ill patients [33,[35][36][37][38][39][40]; thus, it is theoretically reasonable to expect greater effects of melatonin in this setting. ...
Melatonin modulates the circadian rhythm and has been studied as a preventive measure against the development of delirium in hospitalized patients. Such an effect may be more evident in patients admitted to the ICU, but findings from the literature are conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether melatonin or ramelteon (melatonin agonist) reduce delirium incidence as compared to a placebo in ICU patients. Secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV) and mortality. Estimates are presented as risk ratio (RR) or mean differences (MD) with 95% confidence interval (CI). Nine RCTs were included, six of them reporting delirium incidence. Neither melatonin nor ramelteon reduced delirium incidence (RR 0.76 (0.54, 1.07), p = 0.12; I 2 = 64%), although a sensitivity analysis conducted adding other four studies showed a reduction in the risk of delirium (RR = 0.67 (95%CI 0.48, 0.92), p = 0.01; I 2 = 67). Among the secondary outcomes, we found a trend towards a reduction in the duration of MV (MD −2.80 (−6.06, 0.47), p = 0.09; I 2 = 94%) but no differences in ICU-LOS (MD −0.26 (95%CI −0.89, 0.37), p = 0.42; I 2 = 75%) and mortality (RR = 0.85 (95%CI 0.63, 1.15), p = 0.30; I 2 = 0%). Melatonin and ramelteon do not seem to reduce delirium incidence in ICU patients but evidence is weak. More studies are needed to confirm this finding.
... A significant role of melatonin treatment in adult insomnia was the conclusion of several recent expert consensus reports [53][54][55][56]. In addition, melatonin reduces the need for sedation in ICU patients [57][58][59][60][61][62]. These chronobiotic/hypnotic effects of melatonin are obtained at a daily dose range of 2-10 mg [63]. ...
Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, “long COVID”. Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or “brain fog”), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration (“brain fog”) and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.
... Maximum peak hormone plasma concentration is around 2-4 a.m. (60 pg/mL) [2,3]. Melatonin therefore plays a decisive role in the physiological control of the circadian sleep-wake cycle [4,5]. ...
Background:
Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro.
Objectives:
The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin.
Methods:
We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3).
Results:
Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance.
Conclusion:
Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.
... Interestingly, independent of light exposure, impaired melatonin secretion has been observed in patients with sepsis [58] and delirium [59,60], highlighting bright light exposure as a potentially important intervention in critically ill patients [56]. Additionally, melatonin and melatonin-receptor agonists are receiving attention as part of ICU-based sleep-wake improvement efforts [61][62][63][64][65][66]. ...
Multiple methods exist for measuring sleep in the intensive care unit (ICU) setting. Although imperfect, the collective picture they provide shows that patients’ sleep is often disrupted and fragmented. Noise, light, care interventions, medications, and mechanical ventilation can all impair sleep in critically ill patients. While human and animal research suggest that poor sleep can affect the entire body, in this chapter we focus on its impact on the immune system and brain, organ systems vital for recovery from critical illness. Further research is needed to define the precise mechanisms and causal relationships between sleep quality and patient outcomes and to implement interventions aimed at improving sleep in the ICU setting.
... Critically ill patients are at high risk of delirium, and hence, any potential benefit of melatonin may be more evident in this population [4, 34,39]. This study was consistent with previous work showing critically ill patients had absent or negligible melatonin levels and enteral melatonin was successfully absorbed [29][30][31][32][33][34]72]. The dose of 4 mg was selected as trials of similar doses (0.5-5 mg) had reported benefit, an excellent safety profile and avoided daytime sedation. ...
Purpose:
Delirium is common in the critically ill, highly distressing to patients and families and associated with increased morbidity and mortality. Results of studies on preventative use of melatonin in various patient groups have produced mixed results. The aim of this study was to determine whether administration of melatonin decreases the prevalence of delirium in critically ill patients.
Methods:
Multicentre, randomized, placebo-controlled, double-blind trial across 12 Australian ICUs recruiting patients from July 2016 to September 2019. Patients of at least 18 years requiring ICU admission with an expected length of stay (LOS) greater than 72 h; enrolled within 48 h of ICU admission. Indistinguishable liquid melatonin (4 mg; n = 419) or placebo (n = 422) was administered enterally at 21:00 h for 14 consecutive nights or until ICU discharge. The primary outcome was the proportion of delirium-free assessments, as a marker of delirium prevalence, within 14 days or before ICU discharge. Delirium was assessed twice daily using the Confusion Assessment Method for ICU (CAM-ICU) score. Secondary outcomes included sleep quality and quantity, hospital and ICU LOS, and hospital and 90-day mortality.
Results:
A total of 847 patients were randomized into the study with 841 included in data analysis. Baseline characteristics of the participants were similar. There was no significant difference in the average proportion of delirium-free assessments per patient between the melatonin and placebo groups (79.2 vs 80% respectively, p = 0.547). There was no significant difference in any secondary outcomes including ICU LOS (median: 5 vs 5 days, p = 0.135), hospital LOS (median: 14 vs 12 days, p = 0816), mortality at any time point including at 90 days (15.5 vs 15.6% p = 0.948), nor in the quantity or quality of sleep. There were no serious adverse events reported in either group.
Conclusion:
Enteral melatonin initiated within 48 h of ICU admission did not reduce the prevalence of delirium compared to placebo. These findings do not support the routine early use of melatonin in the critically ill.
... Melatonin supplementation is known to improve sleep quality in healthy persons and non-critically ill patients (Brzezinski et al. 2005). However, the effects of melatonin and melatonin receptor agonists on sleep quality and outcome of critically ill patients have been inconsistent (Ibrahim et al. 2006, Bourne et al. 2008. Studies on melatonin release in critically ill patients observed that patients exhibited either constantly high or low melatonin levels. ...
Through the application of new technologies and modern data processing with artificial intelligence (AI) capabilities, patient-centered innovations can flourish. Moving forward, patient-centered care must remain the focus of our efforts - digital applications do not fulfil an end in themselves. This volume presents the critical analyses of international experts on the innovative technologies and their integration into acute medicine. It focuses not only on the application of technical components and structures (“tool view”), but also on the incorporation of knowledge in the appropriate environment and context (“ensemble view”). To this effect, the auhors deal with the interdisciplinary and multi-professional possibilities, identify challenges, and consider the responsibilities in guiding innovative approaches in the acute medicine setting, ensuring that it is duly applied for the benefit of the patient.
... Development of this sleep intervention was guided by prior studies demonstrating the feasibility of environmental noise and light reduction strategies (7,18,27,29), use of earplugs, eye masks, and music (20)(21)(22), and pharmacologic sleep aid interventions (48,49). Despite prior studies being limited by sample size (18,22,27,29,48,49), use of simulated ICU settings (20,21), or lack of well-recognized sleep measurement tools (7), they highlighted a spectrum of modifiable ICU sleep factors considered for this project. ...
... Development of this sleep intervention was guided by prior studies demonstrating the feasibility of environmental noise and light reduction strategies (7,18,27,29), use of earplugs, eye masks, and music (20)(21)(22), and pharmacologic sleep aid interventions (48,49). Despite prior studies being limited by sample size (18,22,27,29,48,49), use of simulated ICU settings (20,21), or lack of well-recognized sleep measurement tools (7), they highlighted a spectrum of modifiable ICU sleep factors considered for this project. Prior to QI implementation, sleep and noise ratings, prevalence of delirium/coma within our MICU, and post-ICU cognitive performance and noise ratings closely matched those of prior studies (2, 8, 14, 25-27, 30, 34, 50-52). ...
Background
Delirium is a deleterious condition affecting up to 60% of patients in the surgical intensive care unit (SICU). Few SICU-focused delirium interventions have been implemented, including those addressing sleep-wake disruption, a modifiable delirium risk factor common in critically ill patients.
Research Question
What is the effect on delirium and sleep quality of a multicomponent non-pharmacological intervention aimed at improving sleep-wake disruption in patients in the SICU setting?
Study Design and Methods
Using a staggered pre-post design, we implemented a quality improvement intervention in two SICUs (general surgery/trauma and cardiovascular) in an academic medical center. After a pre-intervention (baseline) period, a multicomponent unit-wide nighttime (i.e., efforts to minimize unnecessary sound and light, provision of earplugs and eye masks) and daytime (i.e., raising blinds, promotion of physical activity) intervention bundle was implemented. A daily checklist was used to prompt staff to complete intervention bundle elements. Delirium was evaluated twice-daily using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Patient sleep quality ratings were evaluated daily using the Richards-Campbell Sleep Questionnaire (RCSQ).
Results
Six hundred and forty-six SICU admissions (332 baseline, 314 intervention) were analyzed. Median [IQR) age was 61 [49, 70] years with 35% females and 83% white race. During the intervention period, patients experienced fewer days of delirium (proportion [±SD] of intensive care unit days = 15% [±27]) as compared to the pre-intervention period (20% [±31]; p=0.022), with an adjusted pre-post decrease of 4.9% [95% CI, 0.5-9.2%], p=0.03). Overall RCSQ perceived sleep quality ratings did not change, but the RCSQ noise subscore increased (9.5% [95% CI, 1.1-17.5%], p=0.02).
Interpretation
Our multicomponent intervention was associated with a significant reduction in the proportion of days patients experienced delirium, reinforcing the feasibility and effectiveness of a non-pharmacological sleep-wake bundle to reduce delirium in critically ill patients in the SICU.
