Delirium, a neuropsychiatric syndrome characterized by an acute and usually reversible state of confusion, while dementia is a chronic, acquired cognitive impairment that significantly reduces a patient's ability to perform daily tasks, learn, work, and engage in social interactions. Previous studies indicates that individuals with dementia are more susceptible to delirium than the general population, and that delirium serves as an independent risk factor for the subsequent onset of dementia. However, a major controversy in this field concerns whether delirium is merely a marker of vulnerability to dementia, or whether delirium-induced adverse outcomes such as falls and functional decline contribute to dementia, or whether delirium directly causes permanent neuronal damage and lead to dementia. It is possible that all these hypotheses hold some truth. In this review, we examine the shared and distinct mechanisms of delirium and dementia by reviewing their clinical features, epidemiology, clinicopathological, biomarkers, neuroimaging, and recent experimental studies, and we discuss the importance of targeting delirium to explore new preventive and therapeutic strategies for reducing long-term cognitive impairment.

Delirium is a common and serious syndrome of acute brain dysfunction associated with negative outcomes. Melatonin may have a role in delirium prevention for critically ill adults based on data from noncritically ill patient populations. Our objective was to assess the feasibility of a multicenter, randomized, placebo-controlled trial testing the hypothesis that low-dose melatonin prevents delirium in adults who are critically ill.

Does low-dose melatonin prevent delirium in critically ill adults?

We conducted this 3-arm feasibility trial in 3 tertiary academic ICUs. Included participants were ≥ 18 years of age, confirmed free of delirium at enrollment, and anticipated to require a > 48-hour ICU stay. We randomized participants to nightly melatonin 0.5 mg, 2 mg, or placebo. Feasibility outcomes were protocol adherence and recruitment rates. Our primary feasibility target was ≥ 85% (± 5% margin of error) of drug doses administered as per protocol. Secondary objectives were to explore adverse drug effects, melatonin pharmacokinetics, and clinical outcomes.

We screened 2,259 patients and excluded 1,863 patients (82.5%), resulting in 396 eligible patients, of whom 71 provided consent, for a recruitment rate of 0.8 patients/mo/site. Median age was 60.5 years (interquartile range [IQR], 48-67 years), and median admission Sequential Organ Failure Assessment score was 7 (IQR, 3-10). Percentage drug administration protocol adherence per patient was a median of 100% (IQR, 92.3%-100%) or a mean of 88.7% (SD, 24.4%). Twenty-five protocol violations occurred, with no differences between groups. Fourteen patients (20%) experienced delirium during the study period and 25 patients (36%) experienced subsyndromal delirium, with no differences between study groups. No serious adverse effects were detected.

Our trial protocol comparing 2 low doses of melatonin and placebo for delirium prevention in critically ill adults demonstrated feasibility for protocol adherence. However, trial eligibility rates were modest primarily because of delirium being present or the inability to screen. Consent rates also were low. This finding suggests that conducting delirium prevention trials that require delirium to be absent on enrollment is particularly challenging in the ICU.

ClinicalTrials.gov; No.: NCT02615340; URL: www.

gov.

Delirium is a complex medical condition marked by acute episodes of cognitive dysfunction and behavioral disturbances, with a multifaceted etiology and challenging management across various clinical settings. Older adults, particularly in postoperative contexts, are at increased risk of developing delirium. Despite extensive research, a single underlying pathophysiological mechanism for delirium remains elusive. However, emerging evidence suggests a correlation between lipid dysregulation and delirium development in elderly patients, especially in postoperative settings. This connection has led to proposed treatments targeting dyslipidemia and associated neuroinflammatory effects in acute-phase delirium. This review aims to synthesize current literature on the relationship between lipid dysregulation and delirium in older adults, highlighting the need for further research into specific neurolipidome constituents and age-related lipid profile changes, potentially uncovering novel therapeutic strategies for delirium.

Delirium is a common and serious condition that frequently affects patients in the intensive care unit (ICU). It is characterised by an acute disturbance in cognition, attention and awareness that develops over a short period of time and tends to fluctuate in severity. Patients with ICU delirium (ICUD) may experience confusion, disorientation, difficulty focusing and perceptual disturbances such as hallucinations or delusions. The prevalence of ICUD is high, with estimates suggesting that it can affect up to 70% of ICU patients. The development of ICUD is associated with several adverse outcomes, including prolonged ICU and hospital stays, increased healthcare costs, higher mortality rates and an increased risk of long-term cognitive impairment, including dementia. It is unclear which components should be included in a complex intervention to prevent and manage ICUD. Furthermore, we need to understand how the different components have been implemented and their impact on clinical practice.

The review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Protocols (PRISMA-P) and the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) reporting recommendations. We will perform systematic searches to identify relevant interventions and implementation strategies for the prevention or management of ICUD. We will assess primary research, service evaluations and audits for the use of the Standards for QUality Improvement Reporting Excellence (SQUIRE) as a checklist for quality improvement in healthcare. We will extract both qualitative and quantitative data and assess study quality using the Critical Appraisal Skills Programme (CASP) tool. Our findings will be synthesised using a best-fit framework synthesis mapped against the Theoretical Domains Framework (TDF). Our Patient and Public Involvement (PPI) group will contribute to the development of review processes such as the research question and methodology and will help to evaluate which outcomes are most important.

No ethical approval is required for this study. The results of this systematic review of implementation strategies will be disseminated through peer-reviewed publications and conferences. They will also form part of an evidence map and logic model for factors that can improve the implementation of strategies for prevention, identification and management of ICUD.

CRD42024537313.

Critically ill adults are at risk for a variety of distressing and consequential symptoms both during and after an ICU stay. Management of these symptoms can directly influence outcomes.

The objective was to update and expand the Society of Critical Care Medicine's 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

The interprofessional inclusive guidelines task force was composed of 24 individuals including nurses, physicians, pharmacists, physiotherapists, psychologists, and ICU survivors. The task force developed evidence-based recommendations using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Conflict-of-interest policies were strictly followed in all phases of the guidelines, including task force selection and voting.

The task force focused on five main content areas as they pertain to adult ICU patients: anxiety (new topic), agitation/sedation, delirium, immobility, and sleep disruption. Using the GRADE approach, we conducted a rigorous systematic review for each population, intervention, control, and outcome question to identify the best available evidence, statistically summarized the evidence, assessed the quality of evidence, and then performed the evidence-to-decision framework to formulate recommendations.

The task force issued five statements related to the management of anxiety, agitation/sedation, delirium, immobility, and sleep disruption in adults admitted to the ICU. In adult patients admitted to the ICU, the task force issued conditional recommendations to use dexmedetomidine over propofol for sedation, provide enhanced mobilization/rehabilitation over usual mobilization/rehabilitation, and administer melatonin. The task force was unable to issue recommendations on the administration of benzodiazepines to treat anxiety, and the use of antipsychotics to treat delirium.

The guidelines task force provided recommendations for pharmacologic management of agitation/sedation and sleep, and nonpharmacologic management of immobility in critically ill adults. These recommendations are intended for consideration along with the patient's clinical status.

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.

Intensive care unit (ICU) delirium is an acute brain dysfunction that affects up to 7 out of 10 patients admitted to ICUs. Patients who develop ICU delirium cannot think clearly, have trouble paying attention, do not understand what is happening around them and may see or hear things that are not there. ICU delirium increases the time patients spend in ICUs and hospitals and therefore healthcare costs. ICU delirium is also associated with increased mortality and dementia in the longer term. ICU delirium prevention and management strategies are likely to include both pharmacological and non-pharmacological components as part of a complex intervention, but it is unclear which components should be included. The objective of this meta-review is to systematically map the quantity and certainty of the available evidence from reviews and meta-analyses of randomised controlled trials (RCTs) of pharmacological and non-pharmacological interventions, which will be used to design a multicomponent intervention to prevent and manage ICU delirium.

A systematic search strategy was performed in MEDLINE (Ovid), Embase (Elsevier), Cochrane Database of Systematic Reviews, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and Web of Science (from inception to 26 September 2023), as well as Epistemonikos (from inception to 19 July 2023). We will include all critically ill adults (aged≥18 years) and any ICU delirium prevention or management intervention (pharmacological or non-pharmacological). For pharmacological interventions, we will include reviews of RCTs. For non-pharmacological interventions, we will consider reviews of RCTs, quasi-experimental and cohort studies. We will use the International Consensus Study (Del-COrS) core outcome set for research evaluating interventions to prevent or manage ICU delirium and synthesise our findings using quantitative data description methods. We will involve our Patient and Public Involvement group of people who experienced ICU delirium to develop and comment on such aspects as the research question, methodology and which outcomes are most important.

No ethical approval is required for this study. The results of this meta-review will be disseminated through peer-reviewed publications and conferences. They will also form part of an evidence map and logic model for the prevention and management of ICU delirium.

CRD42023473260.

New onset insomnia is often experienced by patients during hospitalization due to environmental disruptions, pain and increased patient care activities. Patient distress arising from poor sleep quality and quantity often results in the prescribing of hypnotics. Melatonin use in hospital settings is common and is increasingly used for off label indications including primary insomnia in those aged < 55 years, prevention of delirium and to facilitate benzodiazepine discontinuation. A literature review was conducted to evaluate the efficacy, effectiveness, safety, tolerability, and cost-effectiveness of melatonin for various off-label indications in inpatient hospital settings. The review found limited high quality evidence demonstrating a clinically meaningful benefit from melatonin in improving sleep, delirium, or facilitating benzodiazepine discontinuation in the inpatient setting. Study findings were inconsistent, and those that did show statistical improvement were of uncertain clinical benefit. The review also found a paucity of data on the safety of melatonin when used in hospitalized patients, and no evidence to support cost-effectiveness. Non-pharmacological interventions are recommended as first-line treatment of insomnia and for the prevention of delirium in inpatient settings. The use of interventions without evidence for efficacy or effectiveness is contrary to the quality use of medicines principles in Australia's National Medicines Policy. Context-specific evidence on the efficacy and effectiveness of a medicine should guide clinician decision-making and prescribing, to improve the quality use of medicines.

Sleep-wake and circadian disruption (SCD) is a core feature of delirium. It has been hypothesized that SCD contributes to delirium pathogenesis; therefore, interventions that prevent or reverse SCD represent an array of promising opportunities in relation to delirium. This review explores the relationship between sleep-wake/circadian physiology and delirium pathophysiology with a focus on neurotransmitter systems. Across potential targets aimed at preventing or treating delirium, three broad approaches are considered: 1. Pharmacological mechanisms that contribute to physiological sleep may preserve or restore next-day cognition in patients with or at risk for delirium (e.g., alpha 2 agonists, dopamine 2 antagonists, serotonin 2 A antagonists, dual orexin receptor antagonists, or GHB agonists); 2. Pharmacological mechanisms that promote wakefulness during the day may combat hypoactive delirium (e.g., adenosine 2 A antagonists, dopamine transporter antagonists, orexin agonists, histamine 3 antagonists); and 3. Melatonergic and other circadian interventions could strengthen the phase or amplitude of circadian rhythms and ensure appropriately entrained timing in patients with or at risk for delirium (e.g., as informed by a person's preexisting circadian phase).

To review causes, risk factors, and consequences of sleep disruption in critically ill patients; evaluate the role of nonpharmacological and pharmacological therapies for management of sleep in the intensive care unit (ICU); and discuss the role of pharmacists in implementation of sleep bundles.

Critically ill patients often have disrupted sleep and circadian rhythm alterations that cause anxiety, stress, and traumatic memories. This can be caused by factors such as critical illness, environmental factors, mechanical ventilation, and medications. Methods to evaluate sleep, including polysomnography and questionnaires, have limitations that should be considered. Multicomponent sleep bundles with a focus on nonpharmacological therapy aiming to reduce nocturnal noise, light, and unnecessary patient care may improve sleep disorders in critically ill patients. While pharmacological agents are often used to facilitate sleep in critically ill patients, evidence supporting their use is often of low quality, which limits use to patients who have sleep disruption refractory to nonpharmacological therapy. Dedicated interprofessional teams are needed for implementation of sleep bundles in the ICU. Extensive pharmacotherapeutic training and participation in daily patient care rounds make pharmacists vital members of the team who can help with all components of the bundle. This narrative review discusses evidence for elements of the multicomponent sleep bundle and provides guidance on how pharmacists can help with implementation of nonpharmacological therapies and management of neuroactive medications to facilitate sleep.

Sleep bundles are necessary for patients in the ICU, and dedicated interprofessional teams that include pharmacists are vital for successful creation and implementation.

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.

Despite the use of multidomain prevention strategies, delirium still frequently occurs in hospitalized adults. With delirium often associated with undesirable symptoms and deleterious outcomes, including cognitive decline, treatment is important. Risk-factor reduction and the protocolized use of multidomain, nonpharmacologic bundles remain the mainstay of delirium treatment. There is a current lack of strong evidence to suggest any pharmacologic intervention to treat delirium will help resolve it faster, reduce its symptoms (other than agitation), facilitate hospital throughput, or improve post-hospital outcomes including long-term cognitive function. With the exception of dexmedetomidine as a treatment of severe delirium-associated agitation in the ICU, current practice guidelines do not recommend the routine use of any pharmacologic intervention to treat delirium in any hospital population. Future research should focus on identifying and evaluating new pharmacologic delirium treatment interventions and addressing key challenges and gaps surrounding delirium treatment research.

Delirium in critical ill patients is a complex and common neurological syndrome in the intensive care unit (ICU) that is caused by a range of structural or functional abnormalities. ICU Delirium is associated with reduced compliance, prolonged hospital stays, greater use or delayed withdrawal of sedatives, higher rates and durations of mechanical ventilation, and higher rates of mortality. The aetiology and pathogenesis of ICU delirium are unclear, and the lack of better prediction, prevention, and treatment measures leads to a non-standardized control of delirium. By searching the relevant literature, we aim in this narrative review to describe progress in the pathogenesis, predictive biomarkers, diagnosis, and treatment of ICU delirium.

Severe acute pancreatitis (SAP) is a life-threatening condition that can require invasive mechanical ventilation (IMV) to ensure adequate oxygenation and ventilation. However, IMV can cause delirium, a temporary and fluctuating state of consciousness disorder, which negatively impacts patient outcomes. Perphenazine, an antipsychotic drug that blocks dopamine receptors, can alleviate symptoms such as irritability and restlessness that caused by delirium. This retrospective study aimed to identify risk factors associated with delirium in SAP patients after extubation and withdrawal from IMV, and to determine whether prophylactic use of perphenazine could reduce the incidence of delirium.

A total of 40 patients with SAP aged 18-75 years who underwent IMV and were successfully extubated offline after treatment were included. Perphenazine was used consistently 2 mg q12 h for 2 days before extubation. The assessment of delirium began after the removal of the endotracheal tube, using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) every 12 h. Patients were divided into delirium (n = 9) and non-delirium (n = 31) groups or perphenazine (n = 22) and non-perphenazine (n = 18) groups. The clinical data of patients upon admission and after extubation between groups were analyzed using SPSS 26 software. Binary logistic regression was used to evaluate the risk factors for delirium.

Patients with a mean age of 42 years and a male to female ratio of 1.58:1 were enrolled. The incidence of delirium was 22.50%. Univariate analysis (P = 0.025) and binary logistic regression (P = 0.035, 95%CI 0.002-0.762) showed that prophylactic use of perphenazine reduced the incidence of delirium. Fentanyl use was a risk factor for delirium in the univariate analysis (P = 0.039). Patients in the delirium group were hospitalized longer than those in the non-delirium group (P < 0.05).

Perphenazine might have a potential effect on post-extubation delirium in SAP patients.

Delirium is an acute, global cognitive disorder syndrome, also known as acute brain syndrome, characterized by disturbance of attention and awareness and fluctuation of symptoms. Its incidence is high among critically ill patients. Once patients develop delirium, it increases the risk of unplanned extubation, prolongs hospital stay, increases the risk of nosocomial infection, post-intensive care syndrome-cognitive impairment, and even death. Therefore, it is of great importance to understand how delirium occurs and to reduce the incidence of delirium in critically ill patients. This paper reviews the potential pathophysiological mechanisms of delirium in critically ill patients, with the aim of better understanding its pathophysiological processes, guiding the formulation of effective prevention and treatment strategies, providing a basis for clinical medication.

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.

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.

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.

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.

Critically ill patients suffer disrupted sleep. Hypnotic medications may improve sleep; however, local epidemiological data regarding the amount of nocturnal time awake and the use of such medications is needed.

Point prevalence study.

Adult ICUs in Australia and New Zealand.

All adult patients admitted to participating Intensive Care Units (ICUs) on the study day.

Time awake overnight (22:00-06:00) was determined by structured nurse observation. The use of enterally administered sedative-hypnotic drugs prior to and during ICU admission was recorded, as was the use of a unit policy and non-pharmacological sleep promotion strategies.

Data were available for 532 patients admitted to 40 ICUs (median age 60 years, 336 (63.2%) male, and 222 (41.7%) invasively ventilated). Forty-eight patients (9.0%) received an enteral pharmacological sleep aid, of which melatonin (28, 5.2%) was most frequently used. Patients not invasively ventilated were observed to be awake overnight for a median of 4.0 h (interquartile range (IQR): 2.5, 5.5), with no difference in those receiving an enteral hypnotic (p = 0.9). Non-pharmacological sleep aids were reportedly not offered or available for 52% (earplugs) and 63% of patients (eye masks). Only 7 (17.5%) participating ICUs had a policy informing sleep-optimising interventions.

Patients not receiving invasive ventilation appeared to spend many nocturnal hours awake. Pharmacological sleep aid administration was not associated with a greater observed time asleep. Most patients did not receive any non-pharmacological aid, and most ICUs did not have a local guideline or unit policy on sleep promotion.

The effect of intraoperative anesthesia depth monitoring on delirium occurrence and improvement of nursing quality in the post-anesthesia care unit (PACU) remains unclear. We aimed to explore the effect of intraoperative anesthesia bispectral index (BIS) monitoring on delirium occurrence and improvement of nursing quality in the PACU for patients recovering from general anesthesia.

 This randomized controlled trial included 120 patients, aged 20-80 years, classified as grades I-III according to the American Society of Anesthesiologists. The BIS-guided group (group B) underwent intraoperative monitoring of BIS anesthesia depth (maintained within the anesthetic range (40-60)). The depth of anesthesia was not monitored in the non-BIS-guided group (group C). The patient's vital signs were recorded at the beginning of the operation (T0), upon entering the PACU (T1), 15 min after extubation (T2), and after leaving the PACU (T3). Delirium score, emergence period (extubation and PACU observation times), and adverse events in the PACU were monitored. The nursing activity score (NAS) was used to evaluate the quality of care.

Group B exhibited significantly lower heart rate and mean arterial pressure at T1 and T2, shorter time to extubation and PACU observation time, and a significantly lower incidence of adverse events than group C. Group B had significantly lower Ricker sedation-agitation scores and a lower incidence of delirium than group C. The NAS was significantly lower for group B than for group C. Patients aged 60-80 years in group C experienced agitation, requiring 30% more frequent assistance from one or two nurses than those in group B.

Intraoperative BIS monitoring can reduce the incidence of adverse events in the PACU, diminish the incidence of delirium during the recovery period in elderly patients, lessen the nursing workload, improve nursing quality, and promote patient rehabilitation, thus meriting clinical application.

This review explores delirium in critically ill patients in the inpatient setting, focusing on its prevention and management. It evaluates the efficacy of both current pharmacological and non-pharmacological interventions, aiming to provide a comprehensive overview.

A systematic literature search was conducted to identify relevant studies investigating the prevention and management of delirium resulting in a final sample of 26 articles for analysis.

Of the 26 articles analyzed for this review (N = 8,831 participants) of controlled trials, 16 studies examined the prevention of delirium, 9 explored the treatment of delirium, and 1 investigated both prevention and treatment of delirium.

Among the reviewed studies, there is evidence that non-pharmacologic methods are effective in the prevention of delirium. Evidence regarding pharmacological interventions for delirium prevention is varied and inconclusive, with some indication that atypical antipsychotics like aripiprazole and quetiapine may reduce the incidence of delirium. Regarding the treatment of delirium, there is limited evidence supporting the use of pharmacological agents. Additional double-blinded, randomized, placebo-controlled clinical trials are needed to investigate the efficacy of pharmacologic agents for diverse hospitalized populations.

The study aimed to decrease noise levels in the ICU, anticipated to have adverse effects on both patients and staff, by implementing enhancements in acoustic design.

Recognizing ICU noise as a significant disruptor of sleep and a potential hindrance to patient recovery, this study was conducted at a 40-bed ICU in Fiona Stanley Hospital in Perth, Australia.

A comprehensive mixed-methods approach was employed, encompassing surveys, site analysis, and acoustic measurements. Survey data highlighted the importance of patient sleep quality, emphasizing the negative impact of noise on work performance, patient connection, and job satisfaction. Room acoustics analysis revealed noise levels ranging from 60 to 90 dB(A) in the presence of patients, surpassing sleep disruption criteria.

Utilizing an iterative 3D design modeling process, the study simulated significant acoustic treatment upgrades. The design integrated effective acoustic treatments within patient rooms, aiming to reduce noise levels and minimize transmission to adjacent areas. Rigorous evaluation using industry-standard acoustic software highlights the design's efficacy in reducing noise transmission in particular. Additionally, cost implications were examined, comparing standard ICU construction with acoustically treated options for new construction and refurbishment projects.

This study provides valuable insights into design-based solutions for addressing noise-related challenges in the ICU. While the focus is on improving the acoustic environment by reducing noise levels and minimizing transmission to adjacent areas. It is important to clarify that direct measurements of patient outcomes were not conducted. The potential impact of these solutions on health outcomes, particularly sleep quality, remains a crucial aspect for consideration.

Older adults may be under-represented in critical care research, and results may not apply to this specific population. Our primary objective was to evaluate the prevalence of inclusion of older adults across critical care trials focused on common ICU conditions or interventions. Our secondary objective was to evaluate whether older age was used as a stratification variable for randomization or outcome analysis.

We performed a systematic review of previously published systematic reviews of randomized controlled trials (RCTs) in critical care. We searched PubMed, Ovid, CENTRAL, and Cochrane from 2009 to 2022. Systematic reviews of any interventions across five topics: acute respiratory distress syndrome (ARDS), sepsis/shock, nutrition, sedation, and mobilization were eligible.

We identified 216 systematic reviews and included a total of 253 RCTs and 113,090 patients. We extracted baseline characteristics and the reported proportion of older adults. We assessed whether any upper age limit was an exclusion criterion for trials, whether age was used for stratification during randomization or data analysis, and if age-specific subgroup analysis was present. The most prevalent topic was sepsis (78 trials, 31%), followed by nutrition (62 trials, 25%), ARDS (39 trials, 15%), mobilization (38 trials, 15%), and sedation (36 trials, 14%). Eighteen trials (7%) had exclusion criteria based on older age. Age distribution with information on older adults prevalence was given in six trials (2%). Age was considered in the analysis of ten trials (5%) using analytic methods to evaluate the outcome stratified by age.

In this systematic review, the proportion of older critically ill patients is undetermined, and it is unclear how age is or is not an effect modifier or to what extent the results are valid for older adult groups. Reporting age is important to guide clinicians in personalizing care. These results highlight the importance of incorporating older critically ill patients in future trials to ensure the results are generalizable to this growing population.

To determine whether enteral melatonin decreases the incidence of delirium in critically ill adults.

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).

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.

Enteral melatonin 3mg is not more effective at decreasing the incidence of delirium than standard care is in critically ill adults.

Nonpharmacologic delirium management is recommended by current guidelines, but studies on the impact of ICU design are still limited. The study's primary purpose was to determine if a multicomponent change in room design prevents ICU delirium. Second, the influence of lighting conditions on serum melatonin was assessed.

Prospective observational cohort pilot study.

The new design concept was established in two two-bed ICU rooms of a university hospital. Besides modifications aimed at stress relief, it includes a new dynamic lighting system.

Seventy-four adult critically ill patients on mechanical ventilation with an expected ICU length of stay of at least 48 hours, treated in modified or standard rooms.

None.

The clinical examination included a prospective assessment for depth of sedation, delirium, and pain every 8 hours using validated scores. Blood samples for serum melatonin profiles were collected every 4 hours for a maximum of three 24-hour periods. Seventy-four patients were included in the analysis. Seventy-six percent ( n = 28) of patients in the standard rooms developed delirium compared with 46% of patients ( n = 17) in the modified rooms ( p = 0.017). Patients in standard rooms (vs. modified rooms) had a 2.3-fold higher delirium severity (odds ratio = 2.292; 95% CI, 1.582-3.321; p < 0.0001). Light intensity, calculated using the measure of circadian effective irradiance, significantly influenced the course of serum melatonin ( p < 0.0001). Significant interactions ( p < 0.001) revealed that differences in serum melatonin between patients in standard and modified rooms were not the same over time but varied in specific periods of time.

Modifications in ICU room design may influence the incidence and severity of delirium. Dedicated light therapy could potentially influence delirium outcomes by modulating circadian melatonin levels.

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.

To analyze the effectiveness of sleep interventions in reducing the incidence and duration of delirium in the ICU.

We searched the PubMed, Embase, CINAHL, Web of Science, Scopus, and Cochrane databases for relevant randomized controlled trials from inception to August 2022. Literature screening, data extraction, and quality assessment were performed independently by two investigators. Data from the included studies were analyzed using Stata and TSA software.

Fifteen randomized controlled trials were eligible. Meta-analysis showed that the sleep intervention was associated with a reduced incidence of delirium in the ICU (RR = 0.73, 95% CI = 0.58 to 0.93, p < 0.001) compared to the control group. The results of the trial sequence analysis further confirm that sleep interventions are effective in reducing the occurrence of delirium. Pooled data from the three dexmedetomidine trials showed significant differences in the incidence of ICU delirium between groups (RR = 0.43, 95% CI = 0.32 to 0.59, p < 0.001). The respective pooled results of other sleep interventions (e.g., light therapy, earplugs, melatonin, and multicomponent nonpharmacologic treatments) did not find a significant effect on reducing the incidence and duration of ICU delirium (p > 0.05).

The current evidence suggests that non-pharmacological sleep interventions are not effective in preventing delirium in ICU patients. However, limited by the number and quality of included studies, future well-designed multicenter randomized controlled trials are still needed to validate the results of this study.

Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment.

Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis.

A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs.

This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

Delirium occurs in critical illness and is associated with poor clinical outcomes, having a longstanding impact on survivors. Understanding the complexity of delirium in critical illness and its deleterious outcome has expanded since early reports. Delirium is a culmination of predisposing and precipitating risk factors that result in a transition to delirium. Known risks range from advanced age, frailty, medication exposure or withdrawal, sedation depth, and sepsis. Because of its multifactorial nature, different clinical phenotypes, and potential neurobiological causes, a precise approach to reducing delirium in critical illness requires a broad understanding of its complexity. Refinement in the categorization of delirium subtypes or phenotypes (i.e., psychomotor classifications) requires attention. Recent advances in the association of clinical phenotypes with clinical outcomes expand our understanding and highlight potentially modifiable targets. Several delirium biomarkers in critical care have been examined, with disrupted functional connectivity being precise in detecting delirium. Recent advances reinforce delirium as an acute, and partially modifiable, brain dysfunction, and place emphasis on the importance of mechanistic pathways including cholinergic activity and glucose metabolism. Pharmacologic agents have been assessed in randomized controlled prevention and treatment trials, with a disappointing lack of efficacy. Antipsychotics remain widely used after "negative" trials, yet may have a role in specific subtypes. However, antipsychotics do not appear to improve clinical outcomes. Alpha-2 agonists perhaps hold greater potential for current use and future investigation. The role of thiamine appears promising, yet requires evidence. Looking forward, clinical pharmacists should prioritize the mitigation of predisposing and precipitating risk factors as able. Future research is needed within individual delirium psychomotor subtypes and clinical phenotypes to identify modifiable targets that hold the potential to improve not only delirium duration and severity, but long-term outcomes including cognitive impairment.

The elderly patients admitted to cardiac intensive care unit (CICU) are at relatively high risk for developing delirium. A simple and reliable predictive model can benefit them from early recognition of delirium followed by timely and appropriate preventive strategies.

To explore the role of frailty in delirium prediction and develop and validate a delirium predictive model including frailty for elderly patients in CICU.

A prospective, observational cohort study.

CICU at China-Japan Friendship Hospital from March 1, 2022 to August 25, 2022 (derivation cohort); CICU at Beijing Anzhen Hospital affiliated to Capital Medical University from March 14, 2023 to May 8, 2023 (external validation cohort).

A total of 236 and 90 participants were enrolled in the derivation and external validation cohorts, respectively. Participants in the derivation cohort were assigned into either the delirium (n = 70) or non-delirium group (n = 166) based on the occurrence of delirium.

The simplified Chinese version of the Confusion Assessment Method for the Diagnosis of Delirium in the Intensive Care Unit was used to assess delirium twice a day at 8:00-10:00 and 18:00-20:00 until the onset of delirium or discharge from the CICU. Frailty was assessed using the FRAIL scale during the first 24 h in the CICU. Other possible risk factors were collected prospectively through patient interviews and medical records review. After processing missing data via multiple imputations, univariate analysis and bootstrapped forward stepwise logistic regression were performed to select optimal predictors and develop the models. The models were internally validated using bootstrapping and evaluated comprehensively via discrimination, calibration, and clinical utility in both the derivation and external validation cohorts.

The study developed D-FRAIL predictive model using FRAIL score, hearing impairment, Acute Physiology and Chronic Health Evaluation-II score, and fibrinogen. The area under the receiver operating characteristic curve (AUC) was 0.937 (95% confidence interval [CI]: 0.907-0.967) and 0.889 (95%CI: 0.840-0.938) even after bootstrapping in the derivation cohort. Inclusion of frailty was demonstrated to improve the model performance greatly with the AUC increased from 0.851 to 0.937 (p < 0.001). In the external validation cohort, the AUC of D-FRAIL model was 0.866 (95%CI: 0.782-0.907). Calibration plots and decision curve analysis suggested good calibration and clinical utility of the D-FRAIL model in both the derivation and external validation cohorts.

For elderly patients in the CICU, FRAIL score is an independent delirium predictor and the D-FRAIL model demonstrates superior performance in predicting delirium.

Circadian dysrhythmias occur commonly in critically ill patients reflecting variable effects of underlying illness, ICU environment, and treatments. We retrospectively analyzed the relationship between clinical outcomes and 24-h urinary 6-sulfatoxymelatonin (aMT6s) excretion profiles in 37 critically ill patients with shock and/or respiratory failure. Nonlinear regression was used to fit a 24-h cosine curve to each patient's aMT6s profile, with rhythmicity determined by the zero-amplitude test. From these curves we determined acrophase, amplitude, phase, and night/day ratio. After assessing unadjusted relationships, we identified the optimal multivariate models for hospital survival and for discharge to home (vs. death or transfer to another facility). Normalized aMT6s rhythm amplitude was greater (p = 0.005) in patients discharged home than in those who were not, while both groups exhibited a phase delay. Patients with rhythmic aMT6s excretion were more likely to survive (OR 5.25) and be discharged home (OR 8.89; p < 0.05 for both) than patients with arrhythmic profiles, associations that persisted in multivariate modelling. In critically ill patients with shock and/or respiratory failure, arrhythmic and/or low amplitude 24-h aMT6s rhythms were associated with worse clinical outcomes, suggesting a role for the melatonin-based rhythm as a novel biomarker of critical illness severity.

Delirium is an acute brain dysfunction. As one of the common psychiatric disorders in ICU, it can seriously affect the prognosis of patients. Hormones are important messenger substances found in the human body that help to regulate and maintain the function and metabolism of various tissues and organs. They are also one of the most commonly used drugs in clinical practice. Recent evidences suggest that aberrant swings in cortisol and non-cortisol hormones might induce severe cognitive impairment, eventually leading to delirium. However, the role of hormones in the pathogenesis of delirium still remains controversial. This article reviews the recent research on risk factors of delirium and the association between several types of hormones and cognitive dysfunction. These mechanisms are expected to offer novel ideas and clinical relevance for the treatment and prevention of delirium.

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.

Delirium is a serious consequence of many acute or worsening chronic medical conditions, a side effect of medications, and a precipitant of worsening functional and cognitive status in older adults. It is a syndrome characterized by fluctuations in cognition and impaired attention that develops over a short period of time in response to an underlying medical condition, a substance (prescribed, over the counter, or recreational), or substance withdrawal and can be multi-factorial. We present a narrative review of the literature on nonpharmacologic and pharmacologic approaches to prevention and treatment of delirium with a focus on older adults as a vulnerable population. Older adult patients are most at risk due to decreasing physiologic reserves, with delirium rates of up to 80% in critical care settings. Presentation of delirium can be hyperactive, hypoactive, or mixed, making identification and study challenging as patients with hypoactive delirium are less likely to come to attention in an inpatient or long-term care setting. Studies of delirium focus on prevention and treatment with nonpharmacological or medication interventions, with the preponderance of evidence favoring multi-component nonpharmacological approaches to prevention as the most effective. Though use of antipsychotic medication in delirium is common, existing evidence does not support routine use, showing no clear benefit in clinically significant outcome measures and with evidence of harm in some studies. We therefore suggest that antipsychotics be used to treat agitation, psychosis, and distress associated with delirium at the lowest effective doses and shortest possible duration and not be considered a treatment of delirium itself. Future studies may clarify the use of other agents, such as melatonin and melatonin receptor agonists, alpha-2 receptor agonists, and anti-epileptics.

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.

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.

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.

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.

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.

Postoperative delirium is an important issue in cancer patients, affecting surgical outcomes and the quality of life. Ramelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors. Clinical trials and observational studies in Japan, including in surgical cancer patients, have shown efficacy of ramelteon in delirium prevention, with no serious safety concerns. However, clinical trials from the USA have reported conflicting results. A Japanese phase II study investigated the efficacy and safety of ramelteon for delirium prevention following gastrectomy in patients aged ≥75 years, with findings suggesting the feasibility of a phase III trial. The aim of this multi-centre, double-blind, randomized placebo-controlled phase III trial is to evaluate the effectiveness and safety of oral ramelteon for postoperative delirium prevention in cancer patients aged ≥65 years as advanced medical care. The trial protocol is described here.

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.

To determine the preventive effect of melatonin on delirium in the intensive care units.

We conducted a systematic search of the PubMed, Cochrane Library, Science, Embase, and CNKI databases, with retrieval dates ranging from the databases' inception to September 2022. Controlled trials on melatonin and placebo for preventing delirium in the intensive care units were included. The meta-analysis was performed using Review Manager software (version 5.3) and Stata software (version 14.0).

Six studies involving 2374 patients were included in the meta-analysis. The results of the meta-analysis showed that melatonin did not reduce the incidence of delirium in ICU patients (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.46 to 1.12; p = 0.14). There was a strong hetero-geneity between the selected studies (I2 = 74%). Subgroup analysis results showed that melatonin reduced the incidence of delirium in cardiovascular care unit (CCU) patients (OR: 0.52; 95% CI: 0.37 to 0.73; p=0.0001), but did not in general intensive care unit (GICU) patients (OR: 1.14; 95% CI: 0.86 to 1.50; p=0.35). In terms of the secondary outcomes, there were no significant differences in all-cause mortality (OR: 0.85; 95% CI: 0.66 to 1.09; p=0.20), length of ICU stay (mean difference [MD]: 0.33; 95% CI: -0.53 to 1.18; p=0.45), or length of hospital stay (MD: 0.51; 95% CI: -1.17 to 2.19; p=0.55).

Melatonin reduced the incidence of delirium in CCU patients, but did not significantly reduce the incidence of delirium in GICU patients.

https://www.crd.york.ac.uk/prospero/, identifier CRD42022367665.