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The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial
Abstract
Objectives:
To evaluate whether the use of exogenous melatonin affects sleep, reduces the prevalence of delirium, and decreases the need for analgosedation and to assess whether serum melatonin indices correlate with exogenous administration in critically ill patients.
Design:
Double-blind, randomized, placebo-controlled study.
Setting:
Multicenter ICUs of two tertiary hospitals.
Patients:
A total of 203 adult patients who were admitted to the ICU and administered with analgesics and/or sedatives.
Interventions:
Oral melatonin (10 mg) or placebo for up to seven consecutive nights.
Measurements and main results:
The number of observed sleeping hours at night was assessed by the bedside nurse. Sleep quality was evaluated using the Richards Campbell Questionnaire Sleep (RCSQ). The prevalence of delirium, pain, anxiety, adverse reactions, duration of mechanical ventilation, length of ICU and hospital stays, and doses of sedative and analgesic drugs administered were recorded. The use of analgesics and sedatives was assessed daily. Melatonin levels were determined by enzyme-linked immunosorbent assay. Based on the RCSQ results, sleep quality was assessed to be better in the melatonin group than that in the placebo group with a mean (SD) of 69.7 (21.2) and 60.7 (26.3), respectively (p = 0.029). About 45.8% and 34.4% of participants in the melatonin and placebo groups had very good sleep (risk ratio, 1.33; 95% CI, 0.94-1.89), whereas 3.1% and 14.6% had very poor sleep (risk ratio, 0.21; 95% CI, 0.06-0.71), respectively. No significant difference was observed regarding the days free of analgesics or sedatives, the duration of night sleep, and the occurrence of delirium, pain, and anxiety. Melatonin serum peak levels at 2 AM were 150 pg/mL (range, 125-2,125 pg/mL) in the melatonin group and 32.5 pg/mL (range, 18.5-35 pg/mL) in the placebo group (p < 0.001).
Conclusions:
Melatonin was associated with better sleep quality, which suggests its possible role in the routine care of critically ill patients in the future.
... Eight studies explored the association between melatonin prescription and delirium [74][75][76][77][78][79][80][81] (see online supplemental etable 7). Patients were primarily recruited from MICUs. ...
... 75 77-79 In most cases, patients were recruited early in their ICU stays (eg, admission); however, Bellapart et al enrolled patients after their acute illness had resolved while patients were weaning from mechanical ventilation. 76 Four of the eight studies were double-blind placebo-controlled trials with variable dosing regimens of melatonin: 3 mg at 21:00 for 5 days, 74 3 mg at 21:00 followed by 0.5 mg every hour until 6 mg per night was reached (unclear duration), 76 10 mg at 20:00 for 7 days, 78 and 4 mg at 21:00 initiated within 48 hours of admission for 14 consecutive nights or until ICU discharge. 81 Most studies evaluated delirium with the CAM-ICU instrument 74-77 79-81 ; one study used ICDSC. ...
... 81 Most studies evaluated delirium with the CAM-ICU instrument 74-77 79-81 ; one study used ICDSC. 78 Two of the eight studies found a decrease in the risk of transitioning to delirium with melatonin administration. 74 75 In the study by Abbasi et al, a modest reduction in delirium was seen over the first 8 days of ICU admission, but these findings were limited to medical as compared with surgical ICU patients. ...
Rationale/Objectives
Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU.
Methods
A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified.
Results
Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging.
Conclusions
This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation.
... One article was excluded because the authors did not report the incidence of delirium but rather the median change in Richmond Agitation-Sedation Scale score [19], which is not a scale usually adopted for delirium assessment. After title and abstract selection, only 13 studies [4,15,[20][21][22][23][24][25][26][27][28][29][30] were judged to be of potential interest for our quantitative analyses. However, when considering the study design as per the PICOS criteria, we included only nine RCTs in the primary analysis [4,15,20,22,23,25,26,28,29], whilst one RCT [24], two retrospective studies [21,27] and one recent conference abstract [30] (RCT) were used for sensitivity analyses only. ...
... After title and abstract selection, only 13 studies [4,15,[20][21][22][23][24][25][26][27][28][29][30] were judged to be of potential interest for our quantitative analyses. However, when considering the study design as per the PICOS criteria, we included only nine RCTs in the primary analysis [4,15,20,22,23,25,26,28,29], whilst one RCT [24], two retrospective studies [21,27] and one recent conference abstract [30] (RCT) were used for sensitivity analyses only. ...
... Abbreviations: CI, confidence interval; M-H, Mantel-Haenszel. (Abbasi et al.[20]), (Gandolfi et al.[23]), (Vijayakumar et al.[22]), (Wibrow et al.[15]), (Yicheng Shi[29]), (Nishikimi et al.[25]). ...
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.
... The results of clinical trials for delirium prevention are conflicting and limited by sample sizes, methodological differences, and patient heterogeneity [41][42][43][44][45][46][47][48][49][50][51][52][53][54]. This large investigator-initiated trial aimed to determine the effect of melatonin when given early on delirium prevalence in critically ill patients. ...
... 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. ICU and reported improved sleep quality but not duration, with Bourne et al. reporting daytime supratherapeutic levels [51,54]. In this trial, 4 mg of melatonin led to high plasma levels when melatonin levels would typically be elevated in a healthy population. ...
... In this trial, 4 mg of melatonin led to high plasma levels when melatonin levels would typically be elevated in a healthy population. Prior trials have returned conflicting results with some contrasting our findings, [41][42][43][44][45][46][47][48]54] and undertaken in various clinical populations with varying methodological approaches. The largest by de Jonghe et al., evaluating 452 patients undergoing acute hip surgery, reported no reduction in delirium with 3 mg of melatonin daily versus placebo for 5 days. ...
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.
... The ICU constitutes a specialized department within the hospital. Conscious patients frequently experience negative psychological emotions, such as anxiety and fear, while those in ICUs often report poor sleep quality [5]. Their sleep patterns are highly dispersed and lack deep restorative rapid eye movement sleep. ...
... Recently, people have become increasingly interested in the mental health outcomes of ICU patients [10]. Recent systematic reviews focus on different aspects of mental health in this population, such as post-traumatic stress disorder and depression [5,9]. However, to the best of our knowledge, there are no published systematic reviews on nonspecific anxiety symptoms and sleep quality in awake patients in the ICU. ...
BACKGROUND
The intensive care unit (ICU) is a specialized hospital department. Awake patients in the ICU frequently encounter adverse psychological states, such as anxiety and fear, often accompanied by poor sleep quality. This situation has garnered significant attention within the medical community.
AIM
To investigate the impact of prospective nursing intervention strategies on the sleep quality and negative emotional state of conscious ICU patients.
METHODS
One hundred and twenty ICU awake patients admitted to our hospital were selected and randomly divided into control (n = 60) and observation (n = 60) groups. Patients in the control group were cared for using the conventional nursing model, while patients in the observation group were cared for using the prospective nursing model. Sleep improvement was assessed using the International Standardized Sleep Efficiency Formula and Pittsburgh Sleep Quality Index (PSQI). The PSQI, Generalized Anxiety Disorder 7-item (GAD-7) scale, Self-Depression Scale (SDS), and satisfaction before and after treatment were used to assess the negative emotional states of patients under the two care models.
RESULTS
Patient satisfaction in the observation group was significantly higher than in the control group. The GAD-7 and SDS scores in the observation group were significantly lower than those in the control group, and the total effective rate of sleep improvement in the observation group was significantly higher than in the control group. After treatment, the PSQI scores of the two groups significantly decreased (P < 0.05). The decrease in the observation group was more significant than that in the control group, and the difference between the two groups was statistically significant.
CONCLUSION
Prospective nursing interventions can improve sleep quality and psychological levels and significantly affect conscious patients in the ICU, which is worthy of clinical application.
... Six of the studies 10,11,15,17,18 reported the duration of mechanical ventilation in 1,335 patients (667 in the melatonin arm and 668 in the placebo arm) as seen in Figure 8. The high heterogeneity (MD: −0.85; 95% CI: From −1.64 to −0.06; p = 0.03; I 2 = 83%) and statistically significant results was observed (Fig. 8). ...
... Eight of the twelve studies 7,[9][10][11]15,17,18 with a cumulative 1,549 patients (773 in the experimental and 776 in the placebo arm) were assessed for ICU mortality. A low heterogeneity (MD: 0.78; 95% CI: 0.56-1.11; ...
Introduction
Delirium, being a common disorder among critically ill patients, has a reported incidence ranging 45–83% in the intensive care unit (ICU) population. The prophylactic use of melatonin and melatonergics has been shown to have a positive effect in reducing the incidence of delirium in many clinical trials. Our study was thus proposed to find out the role of melatonin on the incidence and severity of ICU delirium, ICU and hospital length of stay (LOS), requirement, duration of mechanical ventilation, and ICU mortality.
Methodology
A systematic search of various databases was performed to find out the trials which compare melatonin with a placebo or standard therapy for delirium prevention with the results conveyed as mean differences (MDs) or risk ratios. The statistical software, Review Manager (RevMan, version 5.4), was used for data synthesis.
Results
Twelve studies were included in the meta-analysis. Prophylactic administration of melatonin or ramelteon was not associated with a statistically significant reduction in the incidence of delirium (odds ratio [OR] 0.63; confidence interval [CI]: 0.60, 1.32; p = 0.22), the severity of delirium (MD: 0.22; 95% CI: From −1.36 to 1.81; p = 0.78), ICU LOS (MD: 0.05; 95% CI: From −0.65 to 0.75; p = 0.89), hospital LOS (MD: −1.46; 95% CI: From −4.50 to −1.59; p = 0.35), need for mechanical ventilation (OR: 0.74, 95% CI: 0.38−1.44; p = 0.37), and ICU mortality (MD: 0.78; 95% CI: 0.56; 1.11; p = 0.62). However, a significant reduction in the duration of mechanical ventilation (MD: −0.85; 95% CI: From −1.64 to −0.06; p = 0.03) was found.
Conclusion
Our meta-analysis suggests that melatonin when given prophylactically has no significant role in reducing the incidence and severity of delirium, ICU and hospital LOS, need for mechanical ventilation, duration of mechanical ventilation, and ICU mortality. Further studies are warranted.
How to cite this article
Mukundarajan R, Soni KD, Trikha A. Prophylactic Melatonin for Delirium in Intensive Care Unit: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials. Indian J Crit Care Med 2023;27(9):675–685.
... Studies considering melatonin in adult ICU patients have shown no differences in the occurrence of delirium [20] or the duration of sleep, with one study reporting improvements in subjective sleep quality [21,22]. While sleep and circadian disruption in adult critical illness has been thoroughly explored and is a burgeoning area of research [23], similar work for pediatric critical illness is comparatively sparse (Table 1). ...
... In addition, melatonin administration has been suggested to play an adjunctive role to sedation and analgesia, decreasing nocturnal blood pressure, and decreasing nocturnal seizures in PICU patients [33]. In adult ICU patients, conflicting literature exists, as some studies have failed to show improvements in sleep duration and sleep quality with the use of melatonin and melatonin receptor agonists in adult patients [22,34,35], while one study did find improved sleep quality [21]. As for delirium prevention, a recent meta-analysis found no evidence of a reduction in delirium with melatonin or ramelteon administration in adult ICU patients when considering nine randomized controlled studies. ...
Growing evidence indicates that altered melatonin secretion during critical illness may influence the quality and quantity of sleep, delirium, and overall recovery. However, limited data exist regarding the use of melatonin in pediatric critical illness. Data were reviewed over a 5-year period at a tertiary pediatric intensive care unit for pediatric patients (ages 0–18 years) who were prescribed melatonin with the aim of identifying the frequency of and indications for use. Data collection included the hospital day of initiation, the dose, the frequency, the duration of use, and the length of stay. The results demonstrate that melatonin was infrequently prescribed (6.0% of patients admitted; n = 182) and that the majority of patients received melatonin as continuation of home medication (46%; n = 83 of 182). This group had significantly earlier melatonin use (0.9 ± 2.3 day of hospitalization; p < 0.0001) and significantly reduced lengths of stay compared to the other groups (mean LOS 7.2 ± 9.3 days; p < 0.0001). Frequently, clear documentation of indication for melatonin use was absent (20%; n = 37). In conclusion, given that melatonin is infrequently used within a tertiary PICU with the most common indication as the continuation of home medication, and often without clear documentation for indication, this presents an opportunity to emphasize a more attentive and strategic approach regarding melatonin use in the PICU population.
... Melatonin peaks in low light and is suppressed by daylight; the onset of its secretion positively correlates with sleepiness [73,78]. There are large interindividual differences in the timing of peaks and serum concentration levels of endogenous melatonin [74], with an average plasma concentration between 20 and 70 pg/mL [30,74]. In healthy adults, the natural peak concen-tration of melatonin has been found to vary more than 10-fold between individuals, with an average peak of around 60 pg/mL between 2 and 4 a.m. ...
... More studies have examined melatonin use in ICU and post-operative settings. In two RCTs in the ICU, exogenous melatonin (10 mg) increased sleep by one hour and improved sleep quality (as evaluated by subjective questionnaires and electroencephalographic recordings) compared to placebo [30,89]. Although the limited evidence does suggest that exogenous melatonin alters sleep parameters, it is unknown whether these small differences are clinically meaningful, in particular whether or not they benefit patients in other ways (e.g., time to recovery or hospital discharge, incidence of delirium). ...
In this narrative review, we describe what is known about non-pharmacological and pharmacological treatments for insomnia in medical inpatients, with a focus on melatonin. Hospital-acquired insomnia is common, resulting in shortened total sleep time and more nighttime awakenings. Sleep disturbance has been shown to increase systemic inflammation, pain, and the likelihood of developing delirium in hospital. Treatment for insomnia includes both non-pharmacological and pharmacological interventions, the latter of which requires careful consideration of risks and benefits given the known adverse effects. Though benzodiazepines and non-benzodiazepine benzodiazepine receptor agonists are commonly prescribed (i.e., sedative-hypnotics), they are relatively contraindicated for patients over the age of 65 due to the risk of increased falls, cognitive decline, and potential for withdrawal symptoms after long-term use. Exogenous melatonin has a comparatively low likelihood of adverse effects and drug–drug interactions and is at least as effective as other sedative-hypnotics. Though more research is needed on both its effectiveness and relative safety for inpatients, small doses of melatonin before bedtime may be an appropriate choice for inpatients when insomnia persists despite non-pharmacological interventions.
... Sendo assim, esse estudo sugere que estes pacientes têm um menor nível de produção de melatonina endógena, devido às condições ambientais, assim a suplementação de melatonina foi feita para se analisar os efeitos da suplementação exógena no organismo. Por fim, concluiu-se que a administração de doses de melatonina entre 3 e 30 mg nesses pacientes mostrou a melhoria na qualidade do sono, uma vez que a sua administração foi efetiva na maioria dos pacientes da pesquisa(Gandolfi, 2020).O efeito terapêutico da melatonina associada ao estudo do sono-vigília comportamental, a partir de estudos por Sletten et al. Mostraram-se muito eficientes na promoção de melhora em distúrbios de sono. ...
Objetivo: Este estudo tem como propósito analisar os efeitos do uso terapêutico da melatonina em adultos, observando as possíveis aplicações para garantir a melhoria da qualidade do sono. Metodologia: Trata-se de uma revisão narrativa baseada na literatura especializada, por meio de consulta a livros e artigos científicos selecionados no acervo da Biblioteca Central da Universidade Federal de Alfenas-MG, campus de Alfenas, e em bases de dados como Pubmed, Scielo e Uptodate. Resultados e Discussão: Os estudos encontrados sobre o uso de melatonina exógena sustentam a hipótese de que houve um impacto nos distúrbios do sono em adultos, resultando em melhoria no sono da população analisada nos artigos levantados, que abordavam os efeitos e recomendações da melatonina para o tratamento de diversas comorbidades. Conclusão: Após a análise e estudo dos artigos apresentados, conclui-se que é plausível a utilização terapêutica da melatonina. Ela é eficaz em adultos em dosagens baixas durante o período noturno e por um curto período, uma vez que há poucos estudos que avaliam sua eficácia e efeitos colaterais em uso prolongado. No entanto, demonstraram-se lacunas nas pesquisas sobre a melatonina e sua relação com a qualidade do sono ao considerar aspectos mais amplos, como idade, gênero, etnia, comorbidades, tempo de uso, entre outros fatores.
... More recently, a blinded, parallel-group, placebo-controlled, randomised clinical trial compared 10 mg melatonin to placebo in 203 ICU patients reported a statistically significant improvement in sleep with melatonin represented by an increase in RCSQ by nine points, but no difference in nurse-observed total sleep time [224]. Finally, the Pro-MEDIC study was a multicenter, parallel-group, placebocontrolled randomised clinical trial that included 841 patients and assessed a 4 mg dose of melatonin [225]. ...
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.
... Based on this, many scholars have shifted their attention to the treatment of cancer with melatonin. Several studies indicated that melatonin has benefits in cancer treatment, such as enhancing the therapeutic effect of anticancer drugs and improving cognitive flexibility, attention, sleep quality, insomnia, and quality of life in cancer survivors (40,42,43). However, the bioavailability, pharmacokinetic properties, and interindividual differences of exogenous melatonin deserve further understanding (40). ...
Objective
The study aimed to analyze the research status, hotspots, and frontiers of global research on cancer and sleep through bibliometrics and provide references and guidance for future research.
Methods
The literature regarding cancer and sleep from 2002 to 2022 was searched from the Web of Science Core Collection (WoSCC) database. CiteSpace 5.6.R3 was performed for visualization analysis.
Results
A total of 1,172 publications were identified. The number of publications in the field has gradually increased over the past two decades. The United States had the most prominent contributions. Taipei Medical University and the University of California, San Francisco, and David Gozal were the most prolific institutions and author, respectively. The most published academic journal was Supportive Care in Cancer. The research hotspots can be summarized into the symptom cluster intervention for cancer survivors and the association between cancer and melatonin and/or obstructive sleep apnea (OSA). The complex interaction between cancer and sleep disruption and the influencing factors of sleep quality may be the emerging trends of research.
Conclusion
This study systematically analyzed the hotspots and frontiers in the field of cancer and sleep and called for strengthening cooperation among countries, institutions, and authors. In addition, intervention measures for the cancer symptom cluster, the bioavailability of exogenous melatonin, the causal relationship between OSA and cancer, the mechanism of tumor-induced sleep disruption, the dose–response relationship between sleep duration and cancer risk, and the path relationship between sleep quality influencing factors may be the focus of future research.
... Doses as high as 300 mg via PO without significant clinical effects have been demonstrated [176]. An RCT performed in ICU patients showed median serum melatonin levels of 150 pg/mL (range, 125-2125 pg/mL) with an oral dose of 10 mg [177]. Considering physiologic exerciseinduced melatonin increases to over 200 pg/mL have been demonstrated [89], it is likely that a large portion of the healthy population have experienced similar levels at multiple times in their lives. ...
Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity in the United States and is associated with numerous chronic sequelae long after the point of injury. One of the most common long-term complaints in patients with TBI is sleep dysfunction. It is reported that alterations in melatonin follow TBI and may be linked with various sleep and circadian disorders directly (via cellular signaling) or indirectly (via free radicals and inflammatory signaling). Work over the past two decades has contributed to our understanding of the role of melatonin as a sleep regulator and neuroprotective anti-inflammatory agent. Although there is increasing interest in the treatment of insomnia following TBI, a lack of standardization and rigor in melatonin research has left behind a trail of non-generalizable data and ambiguous treatment recommendations. This narrative review describes the underlying biochemical properties of melatonin as they are relevant to TBI. We also discuss potential benefits and a path forward regarding the therapeutic management of TBI with melatonin treatment, including its role as a neuroprotectant, a somnogen, and a modulator of the circadian rhythm.
... All studies measured sleep using self-reported measurement tools, including the Pittsburgh Sleep Index (PSQI), the Pittsburgh sleep diary tool, and the Richards Campbell Questionnaire Sleep (RCSQ). Overall, a number of supplements was found to be associated with better sleep quality, including natural melatonin, [28] saffron supplementation, [29] L-ornithine, [30] and vitamin D supplementation [31]. On the other hand, Ayurveda (a herbal preparation) was found to have no effect on sleep quality among 120 residents of elderly homes in India [32]. ...
Background:
The emerging research in the literature continues to forecast a drastic and alarming increase in negative mental health and sleep health outcomes among populations, especially after the COVID-19 pandemic, which significantly influenced people's way of life. With mental health pharmaceutical interventions continuing to be stigmatized and inaccessible among populations, natural supplements provide an opportunity for intervention.
Objective:
This study sought to conduct a systematic review of the literature on the most recent comprehensive evidence for which nutritional supplements have the greatest therapeutic impact on symptoms of anxiety, depression, and insomnia.
Methods:
A systematic search of the literature, utilizing several databases, including PubMed and Web of Science, was conducted on 29 April 2022. We used developed keywords and MeSH terms for the search. The study eligibility criteria included (1) a randomized control trial; (2) investigating a plant-based therapeutic or natural supplement as the intervention; (3) measuring at least one health outcome of the following: anxiety symptoms, depressive symptoms, or sleep health outcomes; (4) utilizing validated measurement tools to measure the outcome of interest; (5) written in the English language; (6) peer reviewed; and (7) focused on adults and elderly populations.
Main results:
Following the PRISMA guidelines, 76 studies were included in this review. We used the revised Risk of Bias tool (RoB2) to assess the quality of all included randomized control trials. A qualitative data synthesis was conducted. Overall, we found several valuable insights from the evidence in the literature, including evidence that demonstrates the benefits of probiotics and vitamin B complexes on anxiety symptoms, depressive symptoms, and sleep quality. Implication of Key Findings: This review provides the most updated findings in the literature on the topic, including an abundance of research that was published in the past 5 years. Given the expected rise in negative mental and sleep health outcomes following the pandemic, the supplements and therapeutics identified in this study should be the target of intervention measures to increase their accessibility and affordability and allow them to be incorporated into clinical guidelines of treatment. PROSPERO registration number: CRD42022361130.
... Для восстановления фазности ночного сна возможно применение снотворных средств небе нзодиазепиновой структуры. Для профилактики нарушений циркадности возможно рассмотреть применение мелатонинсодержащих препаратов [120]. Нес мотря на отсутствие статистически доказанных утвержденных рекомендаций по фармакотерапии нарушений сна у пациентов ОАРИТ возможно представить перечень мероприятий по обеспечению гигиены сна пациента ОАРИТ, который продемонстрировал эмпирическую эффективность [29,35]. ...
After discharge from the Intensive Care Unit (ICU), more than 50 % of patients experience pathological symptoms that are not related to the primary emergency but reduce the quality of life and require rehabilitation. Post Intensive Care Syndrome (PIСS) include only those conditions that do not have a direct causal relationship with the emergency con-dition that gave rise to hospitalization in the ICU. The pathophysiological basis of the PICS is the phenomenon of “learned non-use”: a state of artificial limitation of the patient’s motor and cognitive activity as a result of the use of analgoseda-tion, bed rest and immobilization. The clinical picture of PICS is determined by the severity of its individual components, detailed using a package of clinimetric scales. Based on the results of dynamic testing, the PICS severity index is calculat-ed. The sum of the scores in the range from 0 to 10 reflects the severity and effectiveness of rehabilitation measures. For the prevention of PICS, the Union of Rehabilitologists of Russia together with the Federation of Anesthesiologists and Resuscitators of Russia has developed the rehabilitation complex “ReabICU”. In the English-language literature, such a complex is called “Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobil-ity” bundle. ReabICU is a complex of technologically therapeutic and diagnostic modules “positioning and mobilization”, “prevention of dysphagia and nutritional deficiency”, “preven-tion of emotional and cognitive impairment and delirium”, “prevention of loss of self-care skills”. The basis of the mul-tidisciplinary rehabilitation team, which includes a doctor for medical rehabilitation, 2 specialists in physical rehabilita-tion, a specialist in occupation therapy, a medical psycholo-gist, a medical speech therapist, a nurse for medical rehabil-itation. The activity of multidisciplinary rehabilitation team is evaluated on the basis of quality criteria and the achieve-ment of the main goal of ReabICU — the preservation of the premorbid status of the patient’s socialization. © 2022, Practical Medicine Publishing House LLC. All rights reserved.
... Además de mejorar la calidad del sueño, una revisión sistemática (44) de 14 estudios con 1712 participantes demostró que la suplementación con melatonina en pacientes en UCI redujo en un 39% la incidencia general de delirios. Actualmente, se están llevando a cabo dos ensayos clínicos aleatorizados que buscan evaluar el papel de la melatonina en pacientes infectados por COVID-19 (45,46). ...
Contexto: la melatonina fue aislada por primera vez, en 1958, por el dermatólogo Aaron Lerner a partir de una glándula
pineal bovina. Para 1970 se descubrió su rol en la regulación del ritmo circadiano y los estados de sueño-vigilia, papel en
el cual se han enfocado la mayoría de los estudios clínicos. Su síntesis ocurre a partir del triptófano, a través de procesos
de hidroxilación y acetilación, para posteriormente convertirse en melatonina. Desde su descubrimiento, se han planteado
múltiples beneficios biológicos, todos ellos basados en sus efectos como reguladora del estrés oxidativo. Es por ello que los
estudios clínicos demuestran que la suplementación de esta hormona, aparte de regular el ritmo circadiano, tiene potenciales efectos en el manejo de enfermedades crónicas no transmisibles
Objetivo: aportar nueva evidencia acerca de los mecanismos fisiológicos y bioquímicos de la melatonina y controvertir su posible uso terapéutico.
Metodología: revisión bibliográfica en la base de datos PubMed y Scopus utilizando los términos MeSH: “melatonin”,
“circadian clocks”, “circadian rhythm”, “cancer”, “oxidative stress”.
Resultados: existe gran evidencia bibliográfica acerca de la historia de la melatonina y sus posibles efectos metabólicos, los cuales van muy de la mano de su rol como reguladora del ritmo circadiano, por medio de los estados sueño-vigilia y luz-oscuridad.
Conclusiones: la melatonina puede servir como coadyuvante en el manejo de enfermedades crónicas no transmisibles como cáncer, obesidad, hígado graso, mucositis y en manejo de pacientes críticamente enfermos.
Circadian rhythms in humans are biological rhythms that regulate various physiological processes within a 24-hour time frame. Critical illness can disrupt the circadian rhythm, as can environmental and clinical factors, including altered light exposure, organ replacement therapies, disrupted sleep–wake cycles, noise, continuous enteral feeding, immobility, and therapeutic interventions. Nonpharmacological interventions, controlling the ICU environment, and pharmacological treatments are among the treatment strategies for circadian disruption. Nutrition establishes biological rhythms in metabolically active peripheral tissues and organs through appropriate synchronization with endocrine signals. Therefore, adhering to a feeding schedule based on the biological clock, a concept known as “chrononutrition,” appears to be vitally important for regulating peripheral clocks. Chrononutritional approaches, such as intermittent enteral feeding that includes overnight fasting and consideration of macronutrient composition in enteral solutions, could potentially restore circadian health by resetting peripheral clocks. However, due to the lack of evidence, further studies on the effect of chrononutrition on clinical outcomes in critical illness are needed. The purpose of this review was to discuss the role of chrononutrition in regulating biological rhythms in critical illness, and its impact on clinical outcomes.
Background: Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve sleep, although their benefits in the ICU remain uncertain. This review aims to provide a comprehensive assessment of the objective and subjective effects of medications used for sleep in the ICU, as well as their adverse effects. Methods: PubMed, Web of Science, Scopus, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from their inception until June 2023 for comparative studies assessing the effects of pharmacologic sleep aids on objective and subjective metrics of sleep. Results: Thirty-four studies with 3498 participants were included. Medications evaluated were melatonin, ramelteon, suvorexant, propofol, and dexmedetomidine. The majority of studies were randomized controlled trials. Melatonin and dexmedetomidine were the best studied agents. Objective sleep metrics included polysomnography (PSG), electroencephalography (EEG), bispectral index, and actigraphy. Subjective outcome measures included patient questionnaires and nursing observations. Evidence for melatonin as a sleep aid in the ICU was mixed but largely not supportive for improving sleep. Evidence for ramelteon, suvorexant, and propofol was too limited to offer definitive recommendations. Both objective and subjective data supported dexmedetomidine as an effective sleep aid in the ICU, with PSG/EEG in 303 ICU patients demonstrating increased sleep duration and efficiency, decreased arousal index, decreased percentage of stage N1 sleep, and increased absolute and percentage of stage N2 sleep. Mild bradycardia and hypotension were reported as side effects of dexmedetomidine, whereas the other medications were reported to be safe. Several ongoing studies have not yet been published, mostly on melatonin and dexmedetomidine. Conclusions: While definitive conclusions cannot be made for most medications, dexmedetomidine improved sleep quantity and quality in the ICU. These benefits need to be balanced with possible hemodynamic side effects.
RESUMO Objetivo: Determinar se a melatonina enteral diminui a incidência de delirium em adultos em estado grave. Métodos: Neste estudo controlado e randomizado, os adultos foram admitidos à unidade de terapia intensiva e/ou receberam apenas o padrão de cuidado habitual (Grupo Controle) ou o tratamento combinado com 3mg de melatonina enteral uma vez ao dia às 21h (Grupo Melatonina). A ocultação da alocação foi feita por meio de envelopes selados opacos e numerados sequencialmente. O intensivista que avaliou o delirium e o pesquisador que realizou a análise dos dados foram cegados quanto à alocação do grupo. O desfecho primário foi a incidência de delirium dentro de 24 horas de internação na unidade de terapia intensiva. Os desfechos secundários foram a incidência de delirium nos dias 3 e 7, a mortalidade na unidade de terapia intensiva, a duração da internação na unidade de terapia intensiva, a duração da ventilação mecânica e o escore da escala de desfecho de Glasgow (na alta). Resultados: Foram incluídos 108 pacientes na análise final, com 54 sujeitos em cada grupo. Em 24 horas de internação na unidade de terapia intensiva, a incidência de delirium não foi diferente entre os Grupos Melatonina e Controle (29,6% versus 46,2%; RR = 0,6; IC95% 0,38 - 1,05; p = 0,11). Nenhum desfecho secundário apresentou diferenças estatisticamente significativas. Conclusão: Em adultos em estado grave, 3mg de melatonina enteral não foi mais eficaz que os cuidados padrão na redução da incidência de delirium.
Introduction: An increase in blood pressure and heart rate is observed during laryngoscopy and insertion of the endotracheal tube. Melatonin is used for sedation in the Intensive Care Unit. Our study was based on the hypothesis that administrating 3 mg and 6 mg of melatonin 90 minutes before induction attenuates hemodynamic responses encountered during laryngoscopy and intubation. Materials and Methods: Seventy-five adult patients scheduled for elective surgical procedures, ASA I and II, were assigned into 3 groups (25 patients in each group) to receive oral placebo, melatonin 3 mg, or melatonin 6 mg 90 minutes prior to induction of anesthesia. Hemodynamic variables were recorded at baseline, before induction, and at 3, 6, 9, 12, 15, and 30 minutes after induction. Analysis of variance (ANOVA) was used for intergroup analysis of data. Categorical variables were compared using non-parametric tests like the Chi-square test or Fisher's exact test. Bonferroni correction was applied for intergroup analysis. Statistical significance was considered when p < 0.05. Results: An increase in heart rate and blood pressure at 3, 6, and 9 minutes after induction of general anesthesia was observed in the control group compared to the melatonin 3 mg and 6 mg groups administered 90 minutes prior to induction. Oral administration of 6 mg of melatonin was found to provide greater attenuation than 3 mg of melatonin. Conclusion: Oral administration of 3 mg and 6 mg melatonin effectively attenuates the hemodynamic pressor changes observed during laryngoscopy and tracheal intubation.
Objective:
To determine whether enteral melatonin decreases the incidence of delirium in critically ill adults.
Methods:
In this randomized controlled trial, adults were admitted to the intensive care unit and received either usual standard care alone (Control Group) or in combination with 3mg of enteral melatonin once a day at 9 PM (Melatonin Group). Concealment of allocation was done by serially numbered opaque sealed envelopes. The intensivist assessing delirium and the investigator performing the data analysis were blinded to the group allocation. The primary outcome was the incidence of delirium within 24 hours of the intensive care unit stay. The secondary outcomes were the incidence of delirium on Days 3 and 7, intensive care unit mortality, length of intensive care unit stay, duration of mechanical ventilation and Glasgow outcome score (at discharge).
Results:
We included 108 patients in the final analysis, with 54 patients in each group. At 24 hours of intensive care unit stay, there was no difference in the incidence of delirium between Melatonin and Control Groups (29.6 versus 46.2%; RR = 0.6; 95%CI 0.38 - 1.05; p = 0.11). No secondary outcome showed a statistically significant difference.
Conclusion:
Enteral melatonin 3mg is not more effective at decreasing the incidence of delirium than standard care is in critically ill adults.
Introduction
It is important to understand the concept of comfort as a whole to build an assistance intervention plan that meets the person's needs. Therefore, it is necessary to monitor and assess the person's sleep by considering the surrounding environment, to provide a comfortable environment that is quiet and provides privacy, especially in contexts of difficult management of environmental factors in the approach to the person in critical condition.
Objectives
The aims of this study were to map the nursing interventions that promote sleep-promoting environmental comfort in critically ill people and identify the instruments to assess sleep in critically ill people.
Methods
This is a scoping review based on the methodological strategy of the Joanna Briggs Institute for Scoping Reviews. The search was conducted on February 17 and 18, 2022, in the databases CINAHL, Cochrane Library Plus, PubMed, JBI Evidence Synthesis, SciELO, DANS Easy Archive, RCAAP, and DART-Europe using the Boolean phrase search strategy: “Hospital Emergency Service” OR “Critical Care” AND “Sleep” NOT “Children” AND Nurs*. We included all studies, conducted in any contextual setting, in Portuguese, English, or Spanish, on adult patients with acute and/or critical illness in intensive care and/or emergency units, which addressed nursing interventions that contribute to environmental comfort and promote sleep. Studies on pregnant or puerperal women, persons with psychiatric disorders, and those at the end of life or in palliative care were excluded.
Results
Twenty-one articles were included in this scoping review. Three categories of nursing interventions emerged: person centered (14 interventions), environment centered (37 interventions), and nurse role centered (45 interventions). Three categories of instruments for sleep assessment emerged, in particular: quality of sleep (12 instruments), environmental effects on a night's sleep (2 instruments), and influence on sleep practices in the intensive care unit (1 instrument).
Discussion
The use of instruments to monitor comfort and sleep allows for an accurate assessment of the impact of nurses' intervention focusing on sleep-promoting interventions aimed at comfort, for an improvement of sleep in critically ill patients.
Conclusion
The interpretation of the content makes it clear that how critically ill patients in different contexts experience the environmental context positively or negatively conditions their comfort. In this sense, it is essential to reflect on these measures as a team so that everyone can apply them.
Background
The prophylactic effect of exogenous melatonin and melatonin receptor agonists (MMRAs) on postoperative delirium (POD) in elderly patients remains controversial.
Objective
This study aimed to assess the prophylactic effect of MMRAs on POD by conducting a systemic review and meta-analysis of randomized controlled trials (RCTs).
Methods
We systematically searched four electronic databases including PubMed, Web of Science, Cochrane Library, and Embase for the eligible studies up to February 28, 2023. The Cochrane risk of bias tool was used for assessing the risk of bias in the included RCTs. The occurrence of POD was the primary outcome. The quality of evidence was evaluated by Grading of Recommendations Assessment, Development, and Evaluation.
Results
A total of 11 RCTs comprising patients (MMRA group: 777 patients and placebo group: 781 patients) were included. The results of the meta-analysis showed that the MMRA group had a lower occurrence of POD than the placebo group (risk ratio = 0.70, 95% confidence interval: 0.51–0.97, P < 0.05, I² = 59%). The subgroup analysis showed that melatonin significantly reduced the occurrence of POD (moderate-quality evidence), whereas ramelteon and tryptophan had no significant impact (moderate-quality evidence).
Conclusion
Existing evidence suggested that perioperative use of melatonin can prevent POD in elderly patients.
Critical illness and stays in the Intensive Care Unit (ICU) have significant impact on sleep. Poor sleep is common in this setting, can persist beyond acute critical illness, and is associated with increased morbidity and mortality. In the past 5 years, intensive care clinical practice guidelines have directed more focus on sleep and circadian disruption, spurring new initiatives to study and improve sleep complications in the critically ill. The global SARS-COV-2 (COVID-19) pandemic and dramatic spikes in patients requiring ICU level care also brought augmented levels of sleep disruption, the understanding of which continues to evolve. This review aims to summarize existing literature on sleep and critical illness and briefly discuss future directions in the field.
Background: The Society of Critical Care Medicine Clinical Practice Guidelines for Management of Pain, Agitation, Delirium, Immobility, and Sleep recommend protocolized non-pharmacologic sleep improvement. Pharmacologic interventions are frequently initiated to promote sleep but the evidence supporting these strategies remains controversial. Purpose: To systematically search and synthesize evidence evaluating pharmacologic sleep promotion modalities in critically ill adults. Methods: A rapid systematic review protocol was used to search Medline, Cochrane Library, and Embase for reports published through October 2022. We included randomized controlled trials (RCTs) and before-and-after cohort studies evaluating pharmacologic modalities intended to improve sleep in adult intensive care unit (ICU) patients. Sleep-related endpoints were the primary outcome of interest. Study and patient characteristics and relevant safety and non-sleep outcome data were also collected. The Cochrane Collaboration Risk of Bias or Risk of Bias in Non-Randomized Studies of Interventions were used to assess the risk of bias for all included studies. Results: Sixteen studies (75% RCTs) enrolling 2573 patients were included; 1207 patients were allocated to the pharmacologic sleep intervention. Most studies utilized dexmedetomidine (7/16; total n = 505 patients) or a melatonin agonist (6/16; total n = 592 patients). Only half of the studies incorporated a sleep promotion protocol as standard of care. Most (11/16, 68.8%) studies demonstrated a significant improvement in ≥1 sleep endpoint (n = 5 dexmedetomidine, n = 3 melatonin agonists, n = 2 propofol/benzodiazepines). Risk of bias was generally low for RCTs and moderate-severe for cohort studies. Conclusions: Dexmedetomidine and melatonin agonists are the most studied pharmacologic sleep promotion modalities, but current evidence does not support their routine administration in the ICU to improve sleep. Future RCTs evaluating pharmacologic modalities for ICU sleep should consider patients' baseline and ICU risks for disrupted sleep, incorporate a non-pharmacologic sleep improvement protocol, and evaluate the effect of these medication interventions on circadian rhythm, physiologic sleep, patient-perceived sleep quality, and delirium.
Introduction
Environmental, patient, disease, and care‐related factors can lead to sleep disruption in the intensive care unit (ICU). Medication administration is a potentially modifiable factor in this setting that has not been well described as a target for sleep improvement.
Objectives
To determine characteristics of nighttime medication administration practices in the ICU, evaluate the effect on patient perceived sleep, and assess the opportunity for pharmacist‐led nighttime medication administration stewardship.
Methods
This was a multicenter, retrospective, observational cohort study. Patients included for chart review had perceived sleep measured using the Richards‐Campbell Sleep Questionnaire (RCSQ). Data were collected on patient characteristics, ICU exposures, and nighttime medications administered. Four RCSQ groups defined for comparison were RCSQ 0–25 indicating “very poor” sleep, 26–50 “poor” sleep, 51–75 “good” sleep, and 76–100 “very good” sleep.
Results
Overall, 115 patients with RCSQ assessments and 435 nighttime medication administrations were included. Nighttime medications were most commonly cardiovascular (28.9%) and central nervous system (21.4%) agents, administered via intravenous (54.5%) and oral (22.7%) routes. Patient characteristics were comparable between the four groups except for history of head trauma. Patients reporting very poor sleep had a significantly higher median number of nighttime medications administered as compared to patients reporting very good sleep (4.0 [interquartile range (IQR) (2, 6)] vs. 2.5 [IQR 1, 4], adjusted p = 0.048). Approximately three‐quarters of nighttime medications occurred between the hours of 22:00–0:59 and 5:00–5:59. Nearly 40% of nighttime medications could have been retimed for daytime administration.
Conclusions
Unnecessary nighttime medication administration is common and associated with poor patient perceived sleep in the ICU. Pharmacists are well‐positioned to evaluate timing of medication administration and cluster medication‐related care for daytime hours, when appropriate. Nighttime medication stewardship optimization by pharmacists is an opportunity to improve patient perceived sleep in the ICU.
Background
Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD.
Methods
We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys.
Results
We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation.
Conclusions
ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.
This short review aimed at (i) providing an update on the health benefits associated with melatonin supplementation, while (ii) considering future potential research directions concerning melatonin supplementation use relative to Coronavirus disease of 2019 (COVID-19). A narrative review of the literature was undertaken to ascertain the effect of exogenous melatonin administration on humans. Night-time melatonin administration has a positive impact on human physiology and mental health. Indeed, melatonin (i) modulates the circadian components of the sleep-wake cycle; (ii) improves sleep efficiency and mood status; (iii) improves insulin sensitivity; and (iv) reduces inflammatory markers and oxidative stress. Melatonin has also remarkable neuroprotective and cardioprotective effects and may therefore prevent deterioration caused by COVID-19. We suggest that melatonin could be used as a potential therapy in the post-COVID-19 syndrome, and therefore call for action the research community to investigate on the potential use of exogenous melatonin to enhance the quality of life in patients with post-COVID-19 syndrome.
See also Figure 1(Fig. 1).
Background:
Up to 80% of patients in the intensive care unit (ICU) suffer from delirium. Studies on the preventative use of melatonin in the ICU have produced mixed results. We performed a systematic review and meta-analysis to evaluate whether early administration of melatonin reduces the prevalence of delirium in critically ill patients.
Methods:
We searched Medline, Embase, and the Cochrane Library for randomized controlled trials comparing melatonin or melatonin agonists to placebo in ICU setting. The population included adult patients in the ICU. The primary outcome was the prevalence of delirium. Secondary outcomes included duration of delirium, delirium-free day, serum melatonin concentration, need for sedation, duration of mechanical ventilation, hospital and ICU length of stay (LOS), all-cause mortality, sleep quality, and adverse events. Trial sequential analysis (TSA) was performed on the primary outcome to prevent the risk of random error and multiplicity phenomenon as a result of repeated significance testing across all the included trials.
Results:
Twelve trials with a total of 2538 patients were analyzed. When all trials were pooled, the incidence of delirium in ICU patients who received melatonin was significantly lower than in those who received placebo (risk ratio, 0.77; 95% confidence interval: 0.61-0.96; I2 = 56%). There were no significant differences in secondary outcomes including duration of delirium, duration of mechanical ventilation, ICU LOS, hospital LOS, and mortality. TSA indicated that Z-curve crossed the traditional boundary, but did not cross the monitoring boundary for benefit, which indicated that it is still inconclusive that melatonin affects the incidence of delirium.
Conclusions:
This meta-analysis found that early administration of melatonin may result in a decreased delirium prevalence in critically ill patients. However, the sensitivity analysis of high-quality studies did not support this finding. In addition, TSA demonstrated that the result may have false-positive error. Therefore, this finding should be interpreted with caution. Further studies are needed to examine the effectiveness of prophylactic melatonin on the prevalence and duration of ICU delirium in the future.
The relationship between polysomnography-based objective sleep and delirium in the intensive care unit (ICU) is inconsistent across studies, suggesting limitations in manually determining the sleep stage of critically ill patients. We objectively measured 24-h sleep using a single-channel electroencephalogram (SleepScope [SS]) and an under-mattress sleep monitor (Nemuri SCAN [NSCAN]), both of which have independent algorithms that automatically determine sleep and wakefulness. Eighteen patients (median age, 68 years) admitted to the ICU after valvular surgery or coronary artery bypass grafting were included, and their sleep time was measured one day after extubation. The median total sleep times (TSTs) measured by SS (TST-SS) and NSCAN were 548 (48-1050) and 1024 (462-1257) min, respectively. Two patients with delirium during the 24-h sleep measurement had very short TST-SS of 48 and 125 min, and the percentage of daytime sleep accounted for >80% in both SS and NSCAN. This preliminary case series showed marked sleep deprivation and increased rates of daytime sleeping in ICU patients with delirium. Although data accuracy from under-mattress sleep monitors is contentious, automated algorithmic sleep/wakefulness determination using a single-channel electroencephalogram may be useful in detecting delirium in ICU patients and could even be superior to polysomnography.
Delirium, often underdiagnosed in the intensive care unit, is a common complication of critical illness that contributes to significant morbidity and mortality. Clinicians should be aware of common risk factors and triggers and should work to mitigate these as much as possible to reduce the occurrence of delirium. This review first provides an overview of the epidemiology, pathophysiology, evaluation, and consequences of delirium in critically ill patients. Presented next is the current evidence for the pharmacologic management of delirium, focusing on prevention and treatment of delirium in the intensive care unit. It concludes by outlining some emerging treatments of delirium.
Objective
This study systematically reviewed the effect of melatonin (MLT) on quality of life (QoL) and symptoms among patients with cancer.
Design
Systematic review and meta-analysis.
Data sources
Cochrane Library, PubMed, Embase, Web of Science, Medline, CINAHL, Scopus, ClinicalTrials.gov, China Biology Medicine (CBM), ProQuest and Open Grey were searched from inception to November 2021.
Eligibility criteria
We included randomised controlled trials (RCTs) assessing the effects of MLT on QoL, sleep quality, fatigue, depression, pain, stomatitis rate and stomatitis severity in adult patients with cancer, without language restrictions. Studies that reported the effects of MLT along with other interventions and had incomplete or absent outcome data were excluded.
Data extraction and synthesis
Two independent reviewers extracted data, and another two reviewers assessed the risk of bias. The risk of bias for each eligible study was assessed using the Cochrane assessment tool. The mean difference or standard mean difference (SMD) with 95% CIs was used in the computation of continuous variables to synthesise data. The relative risk was used for dichotomous outcomes. Heterogeneity was assessed and quantified (I ² statistic).
Results
A total of 19 qualified studies that included 2101 patients with cancer (MLT: 1078, control: 1023) were included in the meta-analysis. The results indicated that MLT had no significant effect on QoL (SMD=−0.01, 95% CI (−0.14 to 0.11), p=0.83), sleep quality (SMD=−0.18, 95% CI (−0.62 to 0.26), p=0.42), fatigue (SMD=−0.34, 95% CI (−0.73 to 0.06), p=0.10), pain (SMD=−0.34, 95% CI (−0.7 to 0.02), p=0.06) or stomatitis severity (RR=0.78, 95% CI (0.47 to 1.30), p=0.35). MLT reduced stomatitis rate among patients with cancer (RR=0.47, 95% CI (0.26 to 0.88), p=0.02), except those with head and neck cancer (RR=1.09, 95% CI (0.92 to 1.29), p=0.35). MLT eased depression in patients who received administration for more than 14 days (SMD=−0.14, 95% CI (−0.27 to –0.01), p=0.03) and those who underwent surgery (SMD=−0.17, 95% CI (−0.32 to –0.03), p=0.02).
Conclusion
The findings showed that MLT did not improve the QoL, sleep quality, fatigue, pain or stomatitis severity among patients with cancer. It had a limited effect on decreasing the stomatitis rate and easing depression. Different treatments, durations and cancer types were the main sources of heterogeneity. Further large-scale RCTs are urgently needed. In addition, the effects of different combinations of MLT dosage and duration, administration types and joint measures are worthy of further study.
PROSPERO registration number
CRD42021292855.
Sleep deficiency, including circadian disruption, is pervasive in patients admitted to the intensive care unit (ICU). However, sleep is critically important to human health, and leveraging the tremendous potential of sleep promotion to improve critical care outcomes is a goal of ICU clinicians and investigators alike. The risks and mechanisms for ICU sleep and circadian disruption are numerous and include broad categories of patient, environmental, and acute illness factors. However, methodologic limitations, particularly the lack of feasible and rigorous sleep measures, have slowed research progress and limited evidence in support of sleep interventions. Many questions remain regarding the natural history of sleep disruption during the acute and recovery phases of critical illness. Furthermore, it is uncertain which aspects of sleep during critical illness are most tightly linked to patient outcomes. Thus, multicomponent bundles which attempt to address the diverse factors causing ICU sleep disruption are complex, challenging to implement, and possibly focused on domains of ICU sleep disruption that are less relevant to improving critical illness outcomes. With the advent of novel measurement technologies, investigators are poised to overcome the listed challenges, answer these key questions, and translate the promise of ICU sleep promotion into clinical practice.KeywordsSleep deficiency, circadian alignment, circadian amplitude, delirium, implementation, translation, sleep duration, sleep quality
Sleep disruption in the intensive care unit (ICU) is frequent, and after non-pharmacological strategies are optimized, pharmacologic strategies should be considered. Dexmedetomidine, melatonin agonists (melatonin and ramelteon), and gabaminergic agents (i.e., propofol and benzodiazepines) are the most commonly-studied medications to improve sleep in critically ill adults. While some of these agents, when used for sleep, have reduced delirium, none have been consistently shown to improve sleep quality or circadian rhythm alterations. Despite this general lack of evidence, nocturnal neuroactive agents are commonly prescribed to improve sleep in the ICU and often continued beyond ICU discharge. Research is required to identify the ideal efficacy outcome(s) that should be used to evaluate pharmacologic sleep improvement interventions in critically ill adults and what the role is for medication-based sleep improvement interventions in the ICU.KeywordsSleepIntensive careMelatoninRamelteonDexmedetomidinePropofol
This article highlights the need to screen survivors of traumatic orthopedic injuries for postinjury symptoms associated with stressor-related disorders such as acute stress disorder and posttraumatic stress disorder, including pain, sleep disturbances, anxiety, and depression. The authors discuss the presentation of these postinjury symptoms, the instruments used to screen for each, the various pharmacological and nonpharmacological treatments, and the nursing implications for managing postinjury symptoms in traumatic orthopedic injury survivors.
Purpose
To systematically review sleep evaluation, characterize sleep disruption, and explore effects of sleepdisruption on outcomes in adult ICU patients.
Materials and methods
We systematically searched databases from May 1969 to June 2021 (PROSPERO protocol number: CRD42020175581). Prospective and retrospective studies were included studying sleep in critically ill adults, excluding patients with sleep or psychiatric disorders. Meta-regression methods were applied when feasible.
Results
132 studies (8797 patients) were included. Fifteen sleep assessment methods were identified, with only two validated. Patients had significant sleep disruption, with low sleep time, and low proportion of restorative rapid eye movement (REM). Sedation was associated with higher sleep efficiency and sleep time. Surgical versus medical patients had lower sleep quality. Patients on ventilation had a higher amount of light sleep. Meta-regression only suggested an association between total sleep time and occurrence of delirium (p < 0.001, 15 studies, 519 patients). Scarce data precluded further analyses. Sleep characterized with polysomnography (PSG) correlated well with actigraphy and Richards Campbell Sleep Questionnaire (RCSQ).
Conclusions
Sleep in critically ill patients is severely disturbed, and actigraphy and RCSQ seem reliable alternatives to PSG. Future studies should evaluate impact of sleep disruption on outcomes.
Objetivo: Elucidar a eficácia da melatonina na prevenção do delirium em pacientes adultos hospitalizados. Métodos: Trata-se de um estudo de abordagem qualitativa, por meio de uma revisão integrativa de literatura, no qual as bases de dados utilizadas foram: PubMed, Directory of Open Access Journals (DOAJ) e Cochrane Library (CL). Os descritores escolhidos, intermediados pelo operador booleano “AND”, para a busca dos artigos nas plataformas foram “melatonin”, “sleep” e “delirium”. Resultados: Após a aplicação de critérios de inclusão e exclusão, restaram 18 artigos selecionáveis. Dos artigos analisados, 12 não encontraram resultados estatisticamente significativos que justifiquem o uso da melatonina como terapêutica preventiva para o delirium em pacientes hospitalizados; 2 apontaram a capacidade de aumentar a qualidade do sono. Considerações finais: Não há um consenso estabelecido sobre os benefícios da melatonina na prevenção do delirium. Ademais, não existem evidências suficientes para sustentar sua utilização. Novos estudos devem ser conduzidos.
Daytime oral administration of exogenous melatonin or melatonin receptor agonists may induce sleepiness by reducing core body temperature and increasing the distal-proximal skin gradient. Exogenous melatonin has cardioprotective, neuroprotective, and antioxidant properties. Exogenous melatonin supplements are often used for the treatment of insomnia. Melatonin absorption and metabolism are variable in exogenous melatonin formulations. Due to first-pass metabolism, the amount of melatonin entering the systemic circulation reduces after oral ingestion. As a result, the pharmacokinetics and efficacy of the compound are affected. The key to improving present formulations and improving their effect on sleep disorders is to increase melatonin bioavailability. The lack of consistency in effectiveness when treating sleep disorders may be partly explained by inconsistency in the delivery time for oral exogenous melatonin formulations. Besides, exogenous melatonin is well tolerated and has no apparent short-or long-term adverse effects.
Sleep deficiency is a common problem in the hospital setting. Contributing factors include preexisting medical conditions, illness severity, the hospital environment, and treatment-related effects. Hospitalized patients are particularly vulnerable to the negative health effects of sleep deficiency that impact multiple organ systems. Objective sleep measurement is difficult to achieve in the hospital setting, posing a barrier to linking improvements in hospital outcomes with sleep promotion protocols. Key next steps in hospital sleep promotion include improvement in sleep measurement techniques and harmonization of study protocols and outcomes to strengthen existing evidence and facilitate data interpretation across studies.
Background:
Melatonin is widely employed as a hypnotic in various patient groups. In intensive care patients, melatonin seems to be increasingly used due to potential clinical effects and a favorable safety profile.
Objectives:
We aimed to investigate the extend of usage and clinical practice of melatonin therapy in intensive care departments in Denmark.
Design:
Data from regional hospital pharmacies and the Danish Intensive Care Database were used to estimate defined daily dose and defined daily dose per 1000 ICU admission days. Also, related expenses in the period 2015-2019. Finally, a questionnaire describing the clinical practice of melatonin therapy was provided to all Danish intensive care departments.
Principal observations:
The usage of melatonin in intensive care departments in Denmark increased from 21,300 DDD (200.0 DDD per 1000 ICU admission days) in 2015 to 52,170 DDD (560.7 DDD per 1000 ICU admission days) in 2019. A total of 32 ICU departments participated in the study (97% of all Danish ICU departments). All included ICU departments employed melatonin as a hypnotic. Nineteen % of included departments administered melatonin to all admitted patients, whereas 25% of departments rarely administered melatonin. Magistral melatonin 3 mg tablets was the most employed drug dose/formulation. Increased doses of melatonin were administered in selected patients. Melatonin was considered safe by prescribing clinicians.
Conclusions:
Melatonin is widely and increasingly used in Danish intensive care departments. The more than doubled usage of melatonin in the study period advocate for further studies employing validated outcomes of sleep and other patient-relevant outcomes.
Background
Although a previous review illustrated the efficacy of melatonin receptor agonists (MRAs) in preventing delirium, some recent randomized controlled trials (RCTs) did not confirm these effects.
Objectives
This study systematically reviewed the efficacy, acceptability, and tolerability of MRAs for delirium prevention.
Materials and Methods
We searched electronic databases, including Scopus, PubMed, CINAHL, and Controlled Trials Register, from their inception to February 20, 2022. The primary efficacy outcome was delirium incidence rate after MRA administration; relative risks (RRs), overall discontinuation, and discontinuation due to adverse events are also presented.
Results
The overall pooled incidence rates of delirium in MRA-treated and placebo-treated groups were significantly different with RR (95% CI)=0.66(0.52, 0.84, ), I2=59%. Similarly, the incidence rate was significantly lower in the melatonin-treated group than in the placebo-treated group [RR (95% CI) =0.65 (0.49, 0.88), I2=65%]. Unfortunately, incidence rates were not significantly different between ramelteon-treated and placebo-treated groups [RR (95% CI) =0.67 (0.42, 1.08), I2=50%]. The pooled incidence rate of delirium of either Melatonin- or Ramelteon--the treated group was not significantly different from the placebo-treated group in elderly patients. The pooled incidence rate of delirium was significantly lower in the melatonin-treated group than in the benzodiazepine-treated group.
Conclusion
Based on this review, Melatonin, could prevent delirium with a small effect size. However, Ramelteon did not show efficacy in preventing delirium. Additionally, either Melatonin or Ramelteon individually, did not show effectiveness in preventing delirium in elderly patients. Therefore, using MRAs to prevent delirium in clinical practice should be cautious. However, future well-defined and large sample size studies could verify these findings.
Background
It is imperative to identify potential biomarkers for early diagnosis and intervention of severe sepsis. This study investigated the relationship between melatonin secretion and outcome of sepsis after 28-day admission.
Methods
Patients with sepsis were randomly divided into an eye mask group and a control group. Blood and urine samples were collected from day 0 to 4. Relevant clinical data and 28-day survival data were obtained. Serum melatonin and urine 6-hydroxy sulfate melatonin (6-SMT) levels were measured.
Results
The outcome of sepsis did not differ between the eye mask and control groups. Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were significantly higher and monocyte human leukocyte antigen-DR (mHLA-DR), serum melatonin, nocturnal urine 6-SMT, and 24-hour urine 6-SMT levels were significantly lower in the nonsurvivors than in the survivors. The outcome at day 28 after admission was significantly associated with APACHE II and SOFA scores and mHLA-DR, nocturnal urine 6-SMT, and 24-hour urine 6-SMT levels. The areas under the receiver operating characteristic curve were 0.785, 0.740, 0.774, and 0.858 for APACHE II score, SOFA score, mHLA-DR expression, and nocturnal urine 6-SMT amount, respectively. The optimal thresholds for mHLA-DR and nocturnal urine 6-SMT were 30.13% and 43.60%, respectively. Nocturnal urine 6-SMT level was significantly and positively correlated with mHLA-DR expression.
Conclusion
Nocturnal urine 6-SMT level may be a feasible biomarker to predict the outcome of patients with sepsis. The use of a night-time eye mask has no significant effect on the outcome of sepsis.
Clinical trials
This study was registered at clinicaltrials.gov (NCT02304224).
Delirium, an acute disturbance in mental status due to another medical condition, is common and morbid in the intensive care unit. Despite its clear association with multiple common risk factors and important outcomes, including mortality and long-term cognitive impairment, both the ultimate causes of and ideal treatments for delirium remain unclear. Studies suggest that neuroinflammation, hypoxia, alterations in energy metabolism, and imbalances in multiple neurotransmitter pathways contribute to delirium, but commonly used treatments (e.g., antipsychotic medications) target only one or a few of these potential mechanisms and are not supported by evidence of efficacy. At this time, the optimal treatment for delirium during critical illness remains avoidance of risk factors, though ongoing trials may expand on the promise shown by agents such as melatonin and dexmedetomidine.
Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Objective:
To review evidence for intensive care unit (ICU) sleep improvement bundle use, identify preferred sleep bundle components and implementation strategies, and highlight the role for pharmacists in developing and evaluating bundle efforts.
Data sources:
Multiple databases were searched from January 1, 1990, to September 1, 2021, using the MeSH terms sleep, intensive care or critical care, protocol or bundle to identify comparative studies evaluating ICU sleep bundle implementation.
Study selection and data extraction:
Study screening, data extraction, and risk-of-bias evaluation were conducted in tandem. The ICU quality improvement literature and Institute for Healthcare Improvement bundle improvement guidance were also reviewed to identify recommended strategies for successful sleep bundle use.
Data synthesis:
Nine studies (3 randomized, 1 quasi-experimental, 5 before-and-after) were identified. Bundle elements varied and were primarily focused on nonpharmacological interventions designed to be performed during either the day or night; only 2 studies included a medication-based strategy. Five studies were associated with reduced delirium; 2 studies were associated with improved total sleep time and 2 with improved patient-perceived sleep. Pharmacists were involved directly in 4 studies.
Relevance to patient care and clinical practice:
Sleep improvement bundles are recommended for use in all critically ill adults; specific bundle elements and ICU team member roles should be individualized at the institution/ICU level. Pharmacists can help lead bundle development efforts and routinely deliver key elements.
Conclusions:
Pharmacists can play an important role in the development and implementation of ICU sleep bundles. Further research regarding the relative benefit of individual bundle elements on relevant patient outcomes is needed.
Background
Sleep disruptions in the intensive care unit (ICU) may lead to complications such as delirium. There is limited evidence addressing how sleep aid use before and during ICU admission affects outcomes.
Objective
The purpose of this study is to evaluate the impact of prior-to-admission sleep aid prescribing practices in the ICU on delirium and sleep outcomes.
Methods
A retrospective review was conducted of adult patients admitted to any ICU from January to June 2018 receiving a sleep aid prior to admission. Patients were categorized based on sleep aid continuation, discontinuation, or alteration during the ICU admission. The primary end point was the incidence of delirium. Secondary end points included the incidence of sleep-wake cycle disturbances, delirium scores, and ICU length of stay.
Results
A total of 291 patients were included with 109 in the continued group, 121 in the discontinued group, and 61 in the altered group. There was a similar incidence of delirium at 24 hours ( P = 0.71), 48 hours ( P = 0.60), 72 hours ( P = 0.25), and 5 days ( P = 0.48) after ICU admission. There was also no statistical difference in sleep-wake cycle disturbances or delirium scores at any time point. ICU length of stay was similar between the groups.
Conclusion and Relevance
The incidence of delirium and sleep-wake cycle disturbances was not affected by differences in prior-to-admission sleep aid prescribing patterns during ICU admission.
Delayed awakening is defined as a persistent disorder of arousal or consciousness 48 to 72 h after sedation interruption in critically ill patients. Delayed awakening is either a component of coma or delirium. It results in longer hospital stays and increased mortality. It is therefore a diagnostic, therapeutic and prognostic emergency. In severe brain injured patients, delayed awakening may be related to the primary neurological injury or to secondary systemic insults related to organ failure associated with intensive care. In the present review, we propose diagnostic, therapeutic and prognostic algorithms for managing delayed awaking in neuro-ICU brain injured patients.
Purpose
To compare the effects of prevention interventions on delirium occurrence in critically ill adults.
Methods
MEDLINE, Embase, PsychINFO, CINAHL, Web of Science, Cochrane Library, Prospero, and WHO international clinical trial registry were searched from inception to April 8, 2021. Randomized controlled trials of pharmacological, sedation, non-pharmacological, and multi-component interventions enrolling adult critically ill patients were included. We performed conventional pairwise meta-analyses, NMA within Bayesian random effects modeling, and determined surface under the cumulative ranking curve values and mean rank. Reviewer pairs independently extracted data, assessed bias using Cochrane Risk of Bias tool and evidence certainty with GRADE. The primary outcome was delirium occurrence; secondary outcomes were durations of delirium and mechanical ventilation, length of stay, mortality, and adverse effects.
Results
Eighty trials met eligibility criteria: 67.5% pharmacological, 31.3% non-pharmacological and 1.2% mixed pharmacological and non-pharmacological interventions. For delirium occurrence, 11 pharmacological interventions (38 trials, N = 11,993) connected to the evidence network. Compared to placebo, only dexmedetomidine (21/22 alpha2 agonist trials were dexmedetomidine) probably reduces delirium occurrence (odds ratio (OR) 0.43, 95% Credible Interval (CrI) 0.21–0.85; moderate certainty). Compared to benzodiazepines, dexmedetomidine (OR 0.21, 95% CrI 0.08–0.51; low certainty), sedation interruption (OR 0.21, 95% CrI 0.06–0.69; very low certainty), opioid plus benzodiazepine (OR 0.27, 95% CrI 0.10–0.76; very low certainty), and protocolized sedation (OR 0.27, 95% CrI 0.09–0.80; very low certainty) may reduce delirium occurrence but the evidence is very uncertain. Dexmedetomidine probably reduces ICU length of stay compared to placebo (Ratio of Means (RoM) 0.78, CrI 0.64–0.95; moderate certainty) and compared to antipsychotics (RoM 0.76, CrI 0.61–0.98; low certainty). Sedative interruption, protocolized sedation and opioids may reduce hospital length of stay compared to placebo, but the evidence is very uncertain. No intervention influenced mechanical ventilation duration, mortality, or arrhythmia. Single and multi-component non-pharmacological interventions did not connect to any evidence networks to allow for ranking and comparisons as planned; pairwise comparisons did not detect differences compared to standard care.
Conclusion
Compared to placebo and benzodiazepines, we found dexmedetomidine likely reduced the occurrence of delirium in critically ill adults. Compared to benzodiazepines, sedation-minimization strategies may also reduce delirium occurrence, but the evidence is uncertain.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
Objective:
To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.
Design:
Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017.
Methods:
Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.
Results:
The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.
Conclusions:
We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.
Objective:
Although mechanical ventilation is frequently a life-saving therapy, its use can result in unwanted side effects. It has been well documented that the choice of sedating agent may influence the duration of mechanical ventilation. Melatonin is a sedative and analgesic agent without any respiratory depressant effect which makes it an attractive adjuvant for sedation in the intubated patients. The aim of this study is to evaluate the effect of melatonin on the duration of mechanical ventilation in patients with hemorrhagic stroke.
Methods:
Forty adult intubated patients with hemorrhagic stroke, who were admitted to the Intensive Care Unit (ICU) within 24 h of onset, were enrolled in this randomized double-blind study. Subjects in the melatonin group received 30 mg of melatonin every night throughout the nasogastric tube. Length of ICU stay, mortality, and duration of mechanical ventilation were recorded for all patients.
Findings:
The duration of mechanical ventilation and length of ICU stay were shorter in patients who received melatonin in comparison with the control group, and this difference was statistically significant for the length of ICU stay and marginally significant for the duration of mechanical ventilation. Although not statistically significant, the mortality rate of the control group was 30%, almost double that of the study group (15%).
Conclusion:
Melatonin possesses hypnotic, analgesic, anti-inflammatory, and anti-oxidative properties that distinguish it as an attractive adjuvant in patients under mechanical ventilation. In conclusion, the administration of melatonin may facilitate the weaning process through decreasing the consumption of sedatives with respiratory depressant properties as well as preventing ventilator-associated lung injury.
Critically ill patients have abnormal circadian and sleep homeostasis. This may be associated with higher morbidity and mortality. The aims of this pilot study were (1) to describe melatonin secretion in conscious critically ill mechanically ventilated patients and (2) to describe whether melatonin secretion and sleep patterns differed in these patients with and without remifentanil infusion. Eight patients were included. Blood-melatonin was taken every 4th hour, and polysomnography was carried out continually during a 48-hour period. American Academy of Sleep Medicine criteria were used for sleep scoring if sleep patterns were identified; otherwise, Watson’s classification was applied. As remifentanil was periodically administered during the study, its effect on melatonin and sleep was assessed. Melatonin secretion in these patients followed a phase-delayed diurnal curve. We did not observe any effect of remifentanil on melatonin secretion. We found that the risk of atypical sleep compared to normal sleep was significantly lower ( p<0.001 ) under remifentanil infusion. Rapid Eye Movement (REM) sleep was only observed during the nonsedation period. We found preserved diurnal pattern of melatonin secretion in these patients. Remifentanil did not affect melatonin secretion but was associated with lower risk of atypical sleep pattern. REM sleep was only registered during the period of nonsedation.
Background
Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium.
Methods
This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep.
Discussion
Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU.
Trial registration
Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471. Registered on 20 December 2015.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1751-0) contains supplementary material, which is available to authorized users.
Melatonin is a neurohormone secreted by epiphysis and extrapineal structures. It performs several functions including chronobiotic, antioxidant, oncostatic, immune modulating, normothermal, and anxiolytic functions. Melatonin affects the cardiovascular system and gastrointestinal tract, participates in reproduction and metabolism, and body mass regulation. Moreover, recent studies have demonstrated melatonin efficacy in relation to pain syndromes. The present paper reviews the studies on melatonin use in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The paper discusses the possible mechanisms of melatonin analgesic properties. On one hand, circadian rhythms normalization results in sleep improvement, which is inevitably disordered in chronic pain syndromes, and activation of melatonin adaptive capabilities. On the other hand, there is evidence of melatonin-independent analgesic effect involving melatonin receptors and several neurotransmitter systems.
Poor sleep quality is a consistently reported by patients in the ICU. In such a potentially hostile environment, sleep is extremely fragmented and sleep architecture is unconventional, with a predominance of superficial sleep stages and a limited amount of time spent in the restorative stages. Among the causes of sleep disruption in the ICU are factors intrinsic to the patients and the acute nature of their condition, as well as factors related to the ICU environment and the treatments administered, such as mechanical ventilation and drug therapy. Although the consequences of poor sleep quality for the recovery of ICU patients remain unknown, it seems to influence the immune, metabolic, cardiovascular, respiratory, and neurological systems. There is evidence that multifaceted interventions focused on minimizing nocturnal sleep disruptions improve sleep quality in ICU patients. In this article, we review the literature regarding normal sleep and sleep in the ICU. We also analyze sleep assessment methods; the causes of poor sleep quality and its potential implications for the recovery process of critically ill patients; and strategies for sleep promotion.
Background:
Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness.
Methods:
A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation > 48h and Simplified Acute Physiology Score II > 32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered.
Results:
Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation.
Conclusion:
Long term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.
Aim of the study:
We evaluated the effect of melatonin supplementation on the nutritional status of postmenopausal women.
Material and methods:
The study included 56 women (51-65 years) and 25 healthy women (27-36 years). The emotional state was assessed using Hamilton Depression Rating Scale (HAM-D), the quality of sleep using Insomnia Severity Index (ISI). Body mass index (BMI) and waist-hip ratio (WHR) were also calculated. The patients were divided into 3 groups: group I (control) - 25 women with normal body weight, group II - 26 postmenopausal women with normal body weight, group III - 30 postmenopausal women with high body weight. In women from group II and III, routine laboratory tests, levels of thyroid-stimulating hormone (TSH), 17β-estradiol, prolactin, follicle-stimulating hormone (FSH) and the concentration of 6-hydroxymelatonin sulphate (6-HMS) in day/night urine fractions were determined. On the day of the examination, women remained on a liquid diet (1800 kcal). Next, a balanced diet of 1500 kcal and 5 mg of melatonin administration were recommended. The follow-up examinations were performed after 4, 8, 12, 16, 20 and 24 weeks.
Results:
The patients from groups II and III showed similar mild levels of anxiety and depression and a significant degree of sleep disorders. In group III, lower urinary 6-HMS excretion was observed at night. In both groups a negative correlation was found between urinary 6-HMS excretion and the degree of sleep disorders. After 24 weeks, a statistically significant improvement of quality of sleep was obtained. A negative correlation was detected between urinary 6-HMS excretion and BMI.
Conclusion:
Melatonin supplementation contributed to body weight reduction.
Sleep is an important physiologic process and lack of sleep is associated with a host of adverse outcomes. In addition, both basic and clinical research has documented the important role circadian rhythm plays in biologic function. Critical illness is a time of extreme vulnerability for patients and the important role sleep may play in recovery for ICU patients is just beginning to be explored. This concise clinical review will focus on the current state of research examining sleep in critical illness. We will discuss sleep and circadian rhythm abnormalities that occur in ICU patients and the challenges to measuring alterations in circadian rhythm in critical illness. In addition we will review methods to measure sleep in the ICU including polysomnography, actigraphy and questionnaires. We will discuss data on the impact of potentially modifiable disruptors to patient sleep, such as noise, light and patient care activities, and report on potential methods to improve sleep in the setting of critical illness. Finally we will review the latest literature on sleep disturbances that persist or develop after critical illness.
Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.
A systematic review was conducted using Samueli Institute's Rapid Evidence Assessment of the Literature (REAL(C)) process to determine the evidence base for melatonin as an agent to optimize sleep or improve sleep quality, and generalize the results to a military, civilian, or other healthy, active, adult population. Multiple databases were searched yielding 35 randomized controlled trials (RCTs) meeting the review's inclusion criteria, which were assessed for methodological quality as well as for melatonin effectiveness. The majority of included studies were high quality (83.0%). Overall, there was insufficient evidence to make strong recommendations regarding melatonin usage for any of the categories under review. A weak recommendation was made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy. No recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made. Larger and longer-duration RCTs utilizing well characterized products are needed to warrant melatonin recommendations in young, healthy adults.
Central disinhibition is a mechanism involved in the physiopathology of fibromyalgia. Melatonin can improve sleep quality, pain and pain threshold. We hypothesized that treatment with melatonin alone or in combination with amitriptyline would be superior to amitriptyline alone in modifying the endogenous pain-modulating system (PMS) as quantified by conditional pain modulation (CPM), and this change in CPM could be associated with serum brain-derived neurotrophic factor (BDNF). We also tested whether melatonin improves the clinical symptoms of pain, pain threshold and sleep quality.
Sixty-three females, aged 18 to 65, were randomized to receive bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for a period of six weeks. The descending PMS was assessed with the CPM-TASK. It was assessed the pain score on the Visual Analog Scale (VAS 0-100 mm), the score on Fibromyalgia Impact Questionnaire (FIQ), heat pain threshold (HPT), sleep quality and BDNF serum. Delta values (post- minus pre-treatment) were used to compare the treatment effect. The outcomes variables were collected before, one and six weeks after initiating treatment.
Melatonin alone or in combination with amitriptyline reduced significantly pain on the VAS compared with amitriptyline alone (P < 0.01). The delta values on the VAS scores were-12.85 (19.93),-17.37 (18.69) and-20.93 (12.23) in the amitriptyline, melatonin and melatonin+amitriptyline groups, respectively. Melatonin alone and in combination increased the inhibitory PMS as assessed by the Numerical Pain Scale [NPS(0-10)] reduction during the CPM-TASK:-2.4 (2.04) melatonin + amitriptyline,-2.65 (1.68) melatonin, and-1.04 (2.06) amitriptyline, (P < 0.05). Melatonin + amitriptyline treated displayed better results than melatonin and amitriptyline alone in terms of FIQ and PPT improvement (P < 0.05, fort both).
Melatonin increased the inhibitory endogenous pain-modulating system as assessed by the reduction on NPS(0-10) during the CPM-TASK. Melatonin alone or associated with amitriptyline was better than amitriptyline alone in improving pain on the VAS, whereas its association with amitriptyline produced only marginal additional clinical effects on FIQ and PPT.
Trial registration
Current controlled trail is registered at clinical trials.gov upon under number NCT02041455. Registered January 16, 2014.
The relationship between the prevalence of multiple sclerosis (MS) and sunlight's ultraviolet radiation was proved. Oxidative stress plays a role in the pathogenic traits of MS. Melatonin possesses antioxidative properties and regulates circadian rhythms. Sleep disturbances in MS patients are common and contribute to daytime fatigue. The aim of study was to evaluate 5 mg daily melatonin supplementation over 90 days on serum total oxidant status (TOS), total antioxidant capacity (TAC) and its influence on sleep quality and depression level of MS patients. A case-control prospective study was performed on 102 MS patients and 20 controls matched for age and sex. The Kurtzke's Expanded Disability Status Scale, magnetic resonance imaging examinations, Athens Insomnia Scale (AIS), Beck Depression Inventory questionnaires were completed. Serum TOS and TAC levels were measured. We observed higher serum levels of TOS in all MS groups, while after melatonin treatment the TOS levels significantly decreased. The TAC level was significantly lower only in mitoxantrone-treated group and it increased after melatonin supplementation. A strong positive correlation between T1Gd(+) number lesions and TAC level in interferon-beta-1A group was observed. AIS group mean score above 6 defining insomnia were observed in interferon-beta-1B-group, glatiramer acetate-group and mitoxantrone-group: 6.62 ± 2.88, 8.45 ± 2.07, 11.1 ± 3.25, respectively. After melatonin treatment the AIS mean scores decrease in glatiramer acetate-group and mitoxantrone-group achieving 5.25 ± 1.14 and 7.08 ± 2.39, respectively (p < 0.05). Finding from our study suggest that melatonin can act as an antioxidant and improves reduced sleep quality in MS patients.
Maintaining a stable and adequate sleeping pattern is associated with good health and disease prevention. As a restorative process, sleep is important for supporting immune function and aiding the body in healing and recovery. Aging is associated with characteristic changes to sleep quantity and quality, which make it more difficult to adjust sleep–wake rhythms to changing environmental conditions. Sleep disturbance and abnormal sleep–wake cycles are commonly reported in seriously ill older patients in the intensive care unit (ICU). A combination of intrinsic and extrinsic factors appears to contribute to these disruptions. Little is known regarding the effect that sleep disturbance has on health status in the oldest of old (80+), a group, who with diminishing physiological reserve and increasing prevalence of frailty, is at a greater risk of adverse health outcomes, such as cognitive decline and mortality. Here we review how sleep is altered in the ICU, with particular attention to older patients, especially those aged 80 years. Further work is required to understand what impact sleep disturbance has on frailty levels and poor outcomes in older critically ill patients.
Melatonin is a methoxyindole synthesized within the pineal gland. The hormone is secreted during the night and appears to play multiple roles within the human organism. The hormone contributes to the regulation of biological rhythms, may induce sleep, has strong antioxidant action and appears to contribute to the protection of the organism from carcinogenesis and neurodegenerative disorders.
At a therapeutic level as well as in prevention, melatonin is used for the management of sleep disorders and jet lag, for the resynchronization of circadian rhythms in situations such as blindness and shift work, for its preventive action in the development of cancer, as additive therapy in cancer and as therapy for preventing the progression of Alzheimer’s disease and other neurodegenerative disorders.
Introduction
Many intensive care patients experience sleep disruption potentially related to noise, light and treatment interventions. The purpose of this study was to characterise, in terms of quantity and quality, the sleep of intensive care patients, taking into account the impact of environmental factors.
Methods
This observational study was conducted in the adult ICU of a tertiary referral hospital in Australia, enrolling 57 patients. Polysomnography (PSG) was performed over a 24 hour period to assess the quantity (total sleep time: hh:mm) and quality (percentage per stage, duration of sleep episode) of patients' sleep while in ICU. Rechtschaffen and Kales criteria were used to categorise sleep. Interrater checks were performed. Sound pressure and illuminance levels and care events were simultaneously recorded. Patients reported on their sleep quality in ICU using the Richards Campbell Sleep Questionnaire and the Sleep in Intensive Care Questionnaire. Data were summarized using frequencies and proportions or measures of central tendency and dispersion as appropriate and Cohen's Kappa statistic was used for interrater reliability of the sleep data analysis.
Results
Patients' median total sleep time was 05:00 (IQR: 02:52-07:14). The majority of sleep was stage 1 and 2 (medians: 19 and 73%) with scant slow wave and REM sleep. The median duration of sleep without waking was 00:03. Sound levels were high (mean Leq 53.95 dB(A) during the day and 50.20 dB(A) at night) and illuminance levels were appropriate at night (median <2lux) but low during the day (median: 74.20lux). There was a median 1.7 care events/h. Patients' mean self-reported sleep quality was poor. Interrater reliability of sleep staging was highest for slow wave sleep and lowest for stage 1 sleep.
Conclusions
The quantity and quality of sleep in intensive care patients are poor and may be related to noise, critical illness itself and treatment events that disturb sleep. The study highlights the challenge of quantifying sleep in the critical care setting and the need for alternative methods of measuring sleep. The results suggest that a sound reduction program is required and other interventions to improve clinical practices to promote sleep in intensive care patients. Trial registration: Australian New Zealand clinical trial registry (http://www.anzctr.org.au/): ACTRN12610000688088.
Patients in intensive care units (ICUs) experience severe sleep alterations and conventional sleep scoring rules are difficult to use in these patients. In a previous study, we showed that abnormal sleep EEG and wake EEG patterns could predict the outcome of noninvasive ventilation in a group of patients treated for acute respiratory failure. Our aims were to assess the prevalence of these abnormal sleep/wake EEG patterns in a larger group and search for objective parameters to help their identification.
We reviewed sleep studies previously performed with full polysomnography during 17-h in conscious nonsedated ICU patients receiving invasive ventilation during weaning or noninvasive ventilation for acute respiratory failure.
We included 57 patients. Sleep scoring using conventional rules was not feasible in 16 (28%) patients due to the absence of stage-2 markers. Wake EEG in these 16 patients, although recognizable, showed abnormal features, including decreased reactivity to eye opening and slower peak EEG frequency compared to patients with normal sleep-wake EEGs.
In almost one third of awake mechanically ventilated ICU patients, sleep cannot be classified with standard criteria. Two new states, atypical sleep and pathologic wakefulness, need to be added. We suggest rules for scoring these states. The origin and links with outcomes of these abnormal EEG patterns deserve investigation.
Fast-acting medications for the management of anxiety are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive tool. This study evaluates the psychometric properties of a patient-reported Global Anxiety-Visual Analog Scale (GA-VAS).
Data from a double-blind, randomized, placebo-controlled study of lorazepam and paroxetine in patients with Generalized Anxiety Disorder were analyzed to assess the reliability, validity, responsiveness, and utility of the GA-VAS. The GA-VAS was completed at clinic visits and at home during the first week of treatment. Targeted psychometric analyses--test-retest reliabilities, validity correlations, responsiveness statistics, and minimum important differences--were conducted.
The GA-VAS correlates well with other anxiety measures, at Week 4, r=0.60 (p<0.0001) with the Hamilton Rating Scale for Anxiety and r=0.74 (p<0.0001) with the Hospital Anxiety and Depression Scale-Anxiety subscale. In terms of convergent and divergent validity, the GA-VAS correlated -0.54 (p<0.0001), -0.48 (p<0.0001), and -0.68 (p<0.0001) with the SF-36 Emotional Role, Social Function, and Mental Health subscales, respectively, but correlated much lower with the SF-36 physical functioning subscales. Preliminary minimum important difference estimates cluster between 10 and 15 mm.
The GA-VAS is capable of validly and effectively capturing a reduction in anxiety as quickly as 24 hours post-dose.
Sleep deprivation is extremely common in the intensive care unit (ICU), and this lack of sleep is associated with low melatonin secretion. The objective of the current study was to explore the effect of exogenous melatonin administration on sleep quality in patients hospitalized in the pulmonary intensive care unit (ICU). We performed a double-blind, placebo-controlled study in the pulmonary ICU of a tertiary care hospital. Eight adult patients hospitalized in the pulmonary ICU with respiratory failure caused by exacerbation of chronic obstructive pulmonary disease (COPD) or with pneumonia were studied. Patients received either 3 mg of controlled-release melatonin or a placebo at 22:00, and sleep quality was evaluated by wrist actigraphy. Treatment with controlled-release melatonin dramatically improved both the duration and quality of sleep in this group of patients. Our results suggest that melatonin administration to patients in intensive care units may be indicated as a treatment for sleep induction and resynchronization of the "biologic clock." This treatment may also help in the prevention of the "ICU syndrome" and accelerate the healing process.
Delirium in the intensive care unit is poorly defined. Clinical evaluation is difficult in the setting of unstable, often intubated patients. A screening tool may improve the detection of delirium.
We created a screening checklist of eight items based on DSM criteria and features of delirium: altered level of consciousness, inattention, disorientation, hallucination or delusion, psychomotor agitation or retardation, inappropriate mood or speech, sleep/wake cycle disturbance, and symptom fluctuation. During 3 months, all patients admitted to a busy medical/surgical intensive care unit were evaluated, and the scale score was compared to a psychiatric evaluation.
In 93 patients studied, 15 developed delirium. Fourteen (93%) of them had a score of 4 points or more. This score was also present in 15 (19%) of patients without delirium, 14 of whom had a known psychiatric illness, dementia, a structural neurological abnormality or encephalopathy. A ROC analysis was used to determine the sensitivity and specificity of the screening tool. The area under the ROC curve is 0.9017. Predicted sensitivity is 99% and specificity is 64%.
This study suggests that the Intensive Care Delirium Screening Checklist can easily be applied by a clinician or a nurse in a busy critical care setting to screen all patients even when communication is compromised. The tool can be utilized quickly and helps to identify delirious patients. Earlier diagnosis may lead to earlier intervention and better patient care.
Afew puzzles relating to a small fraction of my endeavors in the 1950s are summarized herein, with answers to a few questions of the Editor-in-Chief, to suggest that the rules of variability in time complement the rules of genetics as a biological variability in space. I advocate to replace truisms such as a relative constancy or homeostasis, that have served bioscience very well for very long. They were never intended, however, to lower a curtain of ignorance over everyday physiology. In raising these curtains, we unveil a range of dynamics, resolvable in the data collection and as-one-goes analysis by computers built into smaller and smaller devices, for a continued self-surveillance of the normal and for an individualized detection of the abnormal. The current medical art based on spotchecks interpreted by reference to a time-unqualified normal range can become a science of time series with tests relating to the individual in inferential statistical terms. This is already doable for the case of blood pressure, but eventually should become possible for many other variables interpreted today only based on the quicksand of clinical trials on groups. These ignore individual differences and hence the individual's needs. Chronomics (mapping time structures) with the major aim of quantifying normalcy by dynamic reference values for detecting earliest risk elevation, also yields the dividend of allowing molecular biology to focus on the normal as well as on the grossly abnormal.
To objectively record sleep patterns in intensive care unit patients using the Bispectral Index as an electroencephalographic measure of sleep and to determine if the sleep pattern is correlated with various clinical factors.
Adult intensive care patients were recruited who were in the recovery phase of their illness and on minimal sedation. The sleep pattern was examined using an overnight recording of the patient's Bispectral Index and submental electromyogram.
Twenty-seven adult patients in a tertiary level general intensive care unit were enrolled. The sleep pattern was examined using an overnight recording of the patient's Bispectral Index and submental electromyogram. No intensive care unit patients showed a completely normal sleep pattern, but about half showed 40-90 min cyclical periods of slow wave sleep that approached a normal sleep pattern.
Traditional classifications of EEG sleep staging are deficient when used to describe sleep in intensive care unit patients.
The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that, within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is the single most accurate marker for assessing the circadian pacemaker. Additionally, melatonin onset has been used clinically to evaluate problems related to the onset or offset of sleep. DLMO is useful for determining whether an individual is entrained (synchronized) to a 24-h light/dark (LD) cycle or is in a free-running state. DLMO is also useful for assessing phase delays or advances of rhythms in entrained individuals. Additionally, it has become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. More recently, DLMO has also been used to assess the chronobiological features of seasonal affective disorder (SAD). DLMO marker is also useful for identifying optimal application times for therapies such as bright light or exogenous melatonin treatment.
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 sedation.
We administered either oral melatonin (3mg) or placebo at 20:00. We collected pre- and post-dosage blood samples on Days 1 and 3 to confirm drug delivery. Primary outcome measure was number of hours of observed sleep at night, assessed by the bedside nurse. Secondary outcome measures included comparison of the incidence of agitation, assessed by score on the Riker Sedation-Agitation Scale, and requirement for sedatives or haloperidol to settle agitation.
Pre-treatment melatonin levels in the two groups were similarly low: 4.8 pg/mL (95% CI, 2.4-7.5) for melatonin versus 2.4 (95% CI, 1.6-3.2) for placebo (P=0.13). Post-treatment, melatonin levels increased significantly in the melatonin group compared with the placebo group (3543 pg/mL versus 3 pg/mL; P<0.0001). However, subsequent observed nocturnal sleep was similar in the two groups: 240 minutes (range, 75-331.3) for melatonin v 243.4 minutes (range, 0-344.1) for placebo (P=0.98). Observed diurnal sleep was also similar: 138.7 minutes (range, 50-230) with melatonin v 104 minutes (range, 0-485) for placebo (P=0.42). The incidence of agitation was non-significantly higher in the melatonin group (31% v 7%; P=0.11), while the requirement for extra sedation or use of haloperidol was slightly higher in the placebo group (57% versus 46%; P=0.56).
Melatonin is well absorbed, and a standard dose increases blood levels approximately 1000-fold. However, in this pilot assessment, these high levels failed to increase observed nocturnal sleep or induce other observable benefits in tracheostomised ICU patients.
Sleep disturbances are common in critically ill patients and when sleep does occur it traverses the day-night periods. The reduction in plasma melatonin levels and loss of circadian rhythm observed in critically ill patients receiving mechanical ventilation may contribute to this irregular sleep-wake pattern. We sought to evaluate the effect of exogenous melatonin on nocturnal sleep quantity in these patients and, furthermore, to describe the kinetics of melatonin after oral administration in this patient population, thereby guiding future dosing schedules.
We conducted a randomised double-blind placebo-controlled trial in 24 patients who had undergone a tracheostomy to aid weaning from mechanical ventilation. Oral melatonin 10 mg or placebo was administered at 9 p.m. for four nights. Nocturnal sleep was monitored using the bispectral index (BIS) and was expressed in terms of sleep efficiency index (SEI) and area under the curve (AUC). Secondary endpoints were SEI measured by actigraphy and nurse and patient assessments. Plasma melatonin concentrations were measured in nine patients in the melatonin group on the first night.
Nocturnal sleep time was 2.5 hours in the placebo group (mean SEI = 0.26, 95% confidence interval [CI] 0.17 to 0.36). Melatonin use was associated with a 1-hour increase in nocturnal sleep (SEI difference = 0.12, 95% CI -0.02 to 0.27; P = 0.09) and a decrease in BIS AUC indicating 'better' sleep (AUC difference = -54.23, 95% CI -104.47 to -3.98; P = 0.04). Results from the additional sleep measurement methods were inconclusive. Melatonin appeared to be rapidly absorbed from the oral solution, producing higher plasma concentrations relative to similar doses reported in healthy individuals. Plasma concentrations declined biexponentially, but morning (8 a.m.) plasma levels remained supraphysiological.
In our patients, nocturnal sleep quantity was severely compromised and melatonin use was associated with increased nocturnal sleep efficiency. Although these promising findings need to be confirmed by a larger randomised clinical trial, they do suggest a possible future role for melatonin in the routine care of critically ill patients. Our pharmacokinetic analysis suggests that the 10-mg dose used in this study is too high in these patients and may lead to carryover of effects into the next morning. Reduced doses of 1 to 2 mg could be used in future studies.
Current Controlled Trials ISRCTN47578325.
Aim:
The intensive care unit (ICU) environment contributes to the development of sleep disturbances. Sleep disturbances, sleep fragmentation, and multiple awakening episodes lead to the circadian rhythm disorder, which increases the risk of delirium. Melatonin and melatonin receptor agonist is widely used agent in the therapy of sleep disturbances. However, there is also some for its efficacy in ICU delirium. Enteral melatonin and ramelteon supplementation eliminates (partially) the delirium inducing factors.
Methods:
PubMed/MEDLINE, OVID, Embase, Cochrane Library, and Web of Science databases were searched using adequate key words. We reviewed the literature on the role of melatonin and ramelteon in the prevention of sleep disturbances and delirium in intensive care units and analysed the methods of melatonin therapy in an ICU setting. Review followed the PRISMA statement. A review written protocol was not drafted.
Results:
Originally 380 studies were searched in five scientific databases. After rejecting the duplicate results, 125 results were obtained. Finally, 10 scientific studies were included in the review. In selected articles, the leading topics analysed were the role of melatonin and ramelteon in the prevention of delirium and sleep disorders. In addition, the noted effect of therapy with these agents on reducing the ventilation time of mechanical time and the demand for psychoactive substances in the ICU environment.
Conclusion:
Reduction of either the incidence or the severity of delirium course is possible by eliminating its risk factors. Risk factors are directly related to sleep disorders. To reduce the problem, therefore, a holistic approach to the source is necessary. The efficacy of melatonin therapy in an ICU setting requires confirmation in studies including a greater number of participants as the impact of melatonin on these factors is yet to be fully elucidated. However, the prognosis is predictive because this concept provides patients with a minimally invasive and natural form of therapy.
Study objective:
Intensive care unit (ICU) delirium is an acute brain dysfunction that has been associated with increased mortality, prolonged ICU and hospital lengths of stay, and development of post-ICU cognitive impairment. Melatonin may help to restore sleep and reduce the occurrence of ICU delirium. The purpose of this study was to evaluate the effectiveness of melatonin for the prevention of ICU delirium in critically ill adults.
Design:
Retrospective, observational cohort study.
Setting:
Large academic medical center.
Patients:
A total of 232 adults were included who were admitted to the medical-surgical or cardiac ICUs between 2013 and 2017 who had a negative Confusion Assessment Method for the ICU (CAM-ICU). Of those, patients who received melatonin for at least 48 hours were included in the melatonin group (n=117). Patients were included in the control group if they were admitted to the ICU for at least 4 days (average time of melatonin initiation) and did not receive melatonin or antipsychotics within the first 4 days of their ICU stay (n=115).
Measurements and main results:
The primary outcome was development of delirium, which was assessed by using the CAM-ICU twice daily by nursing staff. The development of delirium was significantly lower in the melatonin group: 9 (7.7%) versus 28 (24.3%) patients (p = 0.001). This finding remained significant in multivariate logistic models controlling for age, sex, history of hypertension, need for emergent surgery, Acute Physiology and Chronic Health Evaluation II score, mechanical ventilation, ICU length of stay, dexmedetomidine use, and benzodiazepine use. For those patients who developed delirium, patients in the control group had, on average, 20.9 delirium-free days without coma in 28 days compared with 19.9 days in the melatonin group (p = 0.72). In the melatonin group, melatonin was used for a mean ± SD of 6.3 ± 7.9 days, with a median dose of 3.5 mg/night (range: 1-10 mg).
Conclusion:
The development of ICU delirium was significantly lower in the melatonin group compared with that in the control group. To our knowledge, this is one of the only studies that has examined the use of melatonin for the prevention of ICU delirium. Melatonin may be a promising agent for the prevention of ICU delirium; however, a randomized study is needed to further validate its efficacy.
Objective:
To determine whether treatment of delirium affects outcomes.
Patients and methods:
A retrospective cohort study of patients admitted to the medical intensive care unit (ICU) from July 1, 2015, through June 30, 2016, was conducted. Patients with ICU delirium, defined by a positive Confusion Assessment Method for the ICU score, were included. Patients were stratified into 4 treatment groups based on exposure to melatonin and antipsychotic agents during ICU stay: no pharmacologic treatment, melatonin only, antipsychotics only, and both melatonin and antipsychotics. A time-dependent cause-specific hazards model with death as a competing risk was used to evaluate the effect of melatonin or antipsychotic drug use for delirium on duration of ICU delirium, length of ICU stay, and length of hospitalization. A logistic regression was used to evaluate 28-day mortality. Covariates significantly associated with exposure to melatonin and antipsychotics were included in the minimally adjusted model. Covariates significantly associated in the minimally adjusted model were included in a final adjusted model.
Results:
A total of 449 admissions to the medical ICU were included in the analysis. Exposure to melatonin or antipsychotic agents did not reduce the duration of ICU delirium, ICU/hospital length of stay, or 28-day mortality. However, antipsychotic use only was associated with longer hospitalization.
Conclusion:
Antipsychotic drugs for the treatment ICU delirium may not provide the benefit documented in earlier literature. Further investigation on patient selection, type of antipsychotic, and dosing is needed.
Rationale:
Dexmedetomidine is associated with less delirium than benzodiazepines, and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear.
Objectives:
To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults.
Methods:
This two-center, double-blind, placebo-controlled trial randomized 100 delirium-free critically ill adults receiving sedatives to receive nocturnal (21:30 to 6:15h) intravenous dexmedetomidine (0.2 mcg/kg/min, titrated by 0.1 mcg/kg/min every 15 minutes until a goal RASS = -1 or maximum rate of 0.7 mcg/kg/min was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire (LSEQ).
Measurements and main results:
Nocturnal dexmedetomidine (versus placebo) was associated with a greater proportion of patients who remained delirium-free during the ICU stay [dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients] (RR = 0.44, 95% CI, 0.23 to 0.82, p=0.006). The average LSEQ score was similar [MD 0.02; 95% CI, 0.42 to 1.92] between the 34 dexmedetomidine (average 7 assessments/patient) and 30 placebo (6/patient) group patients able to provide ≥ 1 assessment. Incidence of hypotension, bradycardia or both did not differ significantly between groups.
Conclusions:
Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient-reported sleep quality appears unchanged. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01791296.
General anesthesia is a man-made neurophysiological state comprised of unconsciousness, amnesia, analgesia, and immobility along with maintenance of physiological stability. Growing evidence suggests that anesthetic-induced neural oscillations are a primary mechanism of anesthetic action. Each anesthetic drug class produces distinct oscillatory dynamics that can be related to the circuit mechanisms of drug action. Sleep is a naturally occurring state of decreased arousal that is essential for normal health. Physiological measurements (electrooculogram, electromyogram) and neural oscillatory (electroencephalogram) dynamics are used to empirically characterize sleep into rapid eye movement sleep and the three stages of non-rapid eye movement sleep. In this review, we discuss the differences between anesthesia- and sleep-induced altered states from the perspective of neural oscillations.
The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use.
The review was conducted in accordance to PRISMA guidelines. A systematic literature search was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD), and bioavailability.
The literature search identified 392 records. Twenty-two studies were included in the review. Melatonin dosages varied between 0.3 and 100 mg and were administered either orally or intravenously. Cmax ranged from 72.1 (10 ml/h; 0.02 mg, IV) to 101,163 pg/ml (100 mg, oral). Tmax ranged between 15 (2 mg) and 210 min (10 mg). T1/2 ranged from 28 (0.005 mg, IV) to 126 min (4 mg, oral), whereas AUC ranged between 5400 (0.005 mg, IV) and 6.56 × 10(10) pg/ml × min (1 mg, oral). Cl ranged from 0.97 (0.005 mg, IV) to 132.50 L/min (6 mg, oral), whereas VD ranged between 35 (0.005 mg, IV) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33 %. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination.
Despite methodological differences between the included studies, Tmax was approximately 50 min following oral immediate-release formulations of melatonin. T1/2 was 45 min in both administration routes. Cmax, AUC, Cl, and VD varied extensively between studies. Bioavailability of oral melatonin was approximately 15 %.
Background:
Dexmedetomidine, a potent α-2-adrenergic agonist, is widely used as sedative in critically ill patients. This pilot study was designed to assess the effect of dexmedetomidine administration on sleep quality in critically ill patients.
Methods:
Polysomnography was performed on hemodynamically stable critically ill patients for 57 consecutive hours, divided into three night-time (9:00 PM to 6:00 AM) and two daytime (6:00 AM to 9:00 PM) periods. On the second night, dexmedetomidine was given by a continuous infusion targeting a sedation level -1 to -2 on the Richmond Agitation Sedation Scale. Other sedatives were not permitted.
Results:
Thirteen patients were studied. Dexmedetomidine was given in a dose of 0.6 μg kg(-1) h(-1) (0.4 to 0.7) (median [interquartile range]). Compared to first and third nights (without dexmedetomidine), sleep efficiency was significantly higher during the second night (first: 9.7% [1.6 to 45.1], second: 64.8% [51.4 to 79.9], third: 6.9% [0.0 to 17.1], P < 0.002). Without dexmedetomidine, night-time sleep fragmentation index (7.6 events per hour [4.8 to 14.2]) and stage 1 of sleep (48.0% [30.1 to 66.4]) were significantly higher (P = 0.023 and P = 0.006, respectively), and stage 2 (47.0% [27.5 to 61.2]) showed values lower (P = 0.006) than the corresponding values (2.7 events per hour [1.6 to 4.9], 13.1% [6.2 to 23.6], 80.2% [68.9 to 92.8]) observed with dexmedetomidine. Without sedation, sleep was equally distributed between day and night, a pattern that was modified significantly (P = 0.032) by night-time dexmedetomidine infusion, with more than three quarters of sleep occurring during the night (79% [66 to 87]).
Conclusion:
In highly selected critically ill patients, dexmedetomidine infusion during the night to achieve light sedation improves sleep by increasing sleep efficiency and stage 2 and modifies the 24-h sleep pattern by shifting sleep mainly to the night.
Pain, agitation, and delirium (PAD) occur commonly in critically ill patients. Consequently, analgesic and sedative medications are frequently administered to critically ill patients to treat this pain, agitation or delirium, to improve synchrony with mechanical ventilation, and to decrease the physiologic stress response. But prolonged, continuous deep sedation of ICU patients is associated with numerous adverse outcomes, including longer durations of mechanical ventilation, prolonged ICU stays, acute brain dysfunction, and an increased risk of death. The 2013 ICU PAD Guidelines were developed to provide a clear, evidence-based road map for clinicians to better manage pain, agitation, and delirium in critically ill patients. Significant knowledge gaps in these areas still remain, but if widely adopted, the PAD Guidelines can help bridge these gaps and will be transformative in terms of their impact on ICU care. Strong evidence indicates that linking PAD management strategies with ventilator weaning, early mobility, and sleep hygiene in ICU patients will result in significant synergistic benefits to patient care and reductions in costs. An interdisciplinary team-based approach, using proven process improvement strategies, and ICU patient and family activation and engagement, will help to ensure successful implementation of the ICU PAD Care Bundle in ICUs. This paper highlights the major recommendations of the 2013 ICU PAD Guidelines. We hope this review will help ICU physicians and other health care providers advance the management of pain, agitation and delirium in critically ill patients, and improve patients' clinical outcomes.
Survivors of critical illness are frequently left with long-lasting disability. The association between delirium and disability in critically ill patients has not been described. We hypothesized that the duration of delirium in the ICU would be associated with subsequent disability and worse physical health status following a critical illness.
Prospective cohort study nested within a randomized controlled trial of a paired sedation and ventilator weaning strategy.
A single-center tertiary-care hospital.
One hundred twenty-six survivors of a critical illness.
Confusion Assessment Method for the ICU, Katz activities of daily living, Functional Activities Questionnaire (measuring instrumental activities of daily living), Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score, and Awareness Questionnaire were used. Associations between delirium duration and outcomes were determined via proportional odds logistic regression with generalized estimating equations (for Katz activities of daily living and Functional Activities Questionnaire scores) or via generalized least squares regression (for Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score and Awareness Questionnaire scores). Excluding patients who died prior to follow-up but including those who withdrew or were lost to follow-up, we assessed 80 of 99 patients (81%) at 3 months and 63 of 87 patients (72%) at 12 months. After adjusting for covariates, delirium duration was associated with worse activities of daily living scores (p = 0.002) over the course of the 12-month study period but was not associated with worse instrumental activities of daily living scores (p = 0.15) or worse Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score (p = 0.58). Duration of delirium was also associated with lower Awareness Questionnaire Motor/Sensory Factors scores (p 0.02).
In the setting of critical illness, longer delirium duration is independently associated with increased odds of disability in activities of daily living and worse motor-sensory function in the following year. These data point to a need for further study into the determinants of functional outcomes in ICU survivors.
Our intention was to assess the effectiveness of preoperative oral melatonin medication on sedation, sleep quality, and postoperative analgesia in patients undergoing elective prostatectomy.
Fifty-two ASA I-II patients undergoing elective prostatectomy were included in this study, randomly divided into two groups. Patients received an oral placebo (n = 26) or 6 mg melatonin (n = 26) the night before and 1 h before surgery. All patients received a standard anesthetic protocol. At the end of surgery, all patients received tramadol i.v. via a PCA device. Extubation time, intraoperative fentanyl consumption, and recovery time were assessed at the end of the operation. Pain scores, tramadol consumption, and sedation scores were assessed at 1, 2, 4, 6, 12, 18, and 24 h postoperatively, and sleep quality and subjective analgesic efficacy were assessed at 24 h after surgery.
There were no significant differences in demographic data between the groups. Extubation time and recovery time from anesthesia were significantly longer in the melatonin group (P < 0.05). Intraoperative fentanyl usage, pain scores, and tramadol consumption were significantly lower in the melatonin group (P < 0.05). The postoperative sleep quality of patients was significantly better in the melatonin group than in the control group (P < 0.05). Postoperative VAS of pain was significantly lower in the melatonin group compared with the control group at 1, 2, 4, 6, 12, 18, and 24 h postoperatively (P < 0.05). Subjective analgesic efficacy of patients was significantly different between groups (P < 0.05). The sedation scores were significantly higher in the melatonin group than in the control group at 1 h and 2 h after surgery (P < 0.05).
Preoperative oral melatonin administration decreased pain scores and tramadol consumption and enhanced sleep quality, sedation scores, and subjective analgesic efficacy during the postoperative period.
We determined melatonin reference limits in blood serum of 129 healthy volunteers, aged 21 to 70 years, using enzyme-linked immunosorbent assay (IBL ELISA kit, Hamburg, Germany). At 3:00 AM, in almost full dark, the reference limits were found to be 18.3-134 pg/ml in males, 19.0-197 pg/ml in females and 18.5-180 pg/ml in the whole group. At 8:00 AM, they were statistically lower (5.63-61.8, 3.30-93.2 and 3.83-80.4 pg/ml respectively) possibly due to the light.
The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half-lives. Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%. No difference in serum half-life was seen in any of the study phases. Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both. Further studies examining larger doses, in an attempt to saturate first-pass metabolism if it occurs, may be warranted.
Research to evaluate interventions to promote sleep in critically ill patients has been restricted by the lack of brief, inexpensive outcome measures. This article describes the development and testing of an instrument to measure sleep in critically ill patients. A convenience sample of 70 alert, oriented, critically ill males was studied using polysomnography (PSG), the gold standard for sleep measurement, for one night. In the morning the patients completed the Richards-Campbell Sleep Questionnaire (RCSQ), a five-item visual analog scale. Internal consistency reliability of the RCSQ was .90 and principal components factor analysis revealed a single factor (Eigenvalue = 3.61, percent variance = 72.2). The RCSQ total score accounted for approximately 33% of the variance in the PSG indicator sleep efficiency index (p < .001). The data provide support for the reliability and validity of the RCSQ.
Goal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity.
To test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS).
Prospective cohort study.
Adult medical and coronary ICUs of a university-based medical center.
Thirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001.
Interrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography.
In 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted kappa, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted kappa, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = - 0.31, P<.001), successful extubation (P =.07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications.
The RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.