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Competing Interests: We declare no competing interests.

Delirium, a syndrome characterized by an acute change in attention, awareness and cognition, is caused by a medical condition that cannot be better explained by a pre-existing neurocognitive disorder. Multiple predisposing factors (for example, pre-existing cognitive impairment) and precipitating factors (for example, urinary tract infection) for delirium have been described, with most patients having both types. Because multiple factors are implicated in the aetiology of delirium, there are likely several neurobiological processes that contribute to delirium pathogenesis, including neuroinflammation, brain vascular dysfunction, altered brain metabolism, neurotransmitter imbalance and impaired neuronal network connectivity. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) is the most commonly used diagnostic system upon which a reference standard diagnosis is made, although many other delirium screening tools have been developed given the impracticality of using the DSM-5 in many settings. Pharmacological treatments for delirium (such as antipsychotic drugs) are not effective, reflecting substantial gaps in our understanding of its pathophysiology. Currently, the best management strategies are multidomain interventions that focus on treating precipitating conditions, medication review, managing distress, mitigating complications and maintaining engagement to environmental issues. The effective implementation of delirium detection, treatment and prevention strategies remains a major challenge for health-care organizations globally.

Introduction: Critically ill patients often require sedation for comfort and to facilitate therapeutic interventions. Sedation practice guidelines provide an evidence-based framework with recommendations that can help improve key sedation-related outcomes., Materials and Methods: We conducted a narrative review of current guidelines and recent trials on sedation., Results: From a practice perspective, current guidelines share many limitations including lack of consensus on the definition of light sedation, optimal frequency of sedation assessment, optimal timing for light sedation and consideration of combinations of sedatives. We proposed several strategies to address these limitations and improve outcomes: 1) early light sedation within the first 48 hours with time-weighted monitoring (overall time spent in light sedation in the first 48 hours-sedation intensity-has a dose-dependent relationship with mortality risk, delirium and time to extubation); 2) provision of analgesia with minimal or no sedation where possible; 3) a goal-directed and balanced multimodal approach that combines the benefits of different agents and minimise their side effects; 4) use of dexmedetomidine and atypical antipsychotics as a sedative-sparing strategy to reduce weaning-related agitation, shorten ventilation time and accelerate physical and cognitive rehabilitation; and 5) a bundled approach to sedation that provides a framework to improve relevant clinical outcomes., Conclusion: More effort is required to develop a practical, time-weighted sedation scoring system. Emphasis on a balanced, multimodal appraoch that targets light sedation from the early phase of acute critical illness is important to achieve optimal sedation, lower mortality, shorten time on ventilator and reduce delirium.

Introduction: A study was conducted to describe the sedation practices of intensive care units (ICUs) in Singapore in terms of drug use, sedation depth and the incidence of delirium in both early (< 48 hours) and late (> 48 hours) periods of ICU admission., Methods: A prospective multicentre cohort study was conducted on patients who were expected to be sedated and ventilated for over 24 hours in seven ICUs (surgical ICU, n = 4; medical ICU, n = 3) of four major public hospitals in Singapore. Patients were followed up to 28 days or until ICU discharge, with four-hourly sedation monitoring and daily delirium assessment by trained nurses. The Richmond Agitation and Sedation Scale (RASS) and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were used., Results: We enrolled 198 patients over a five-month period. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25.3 ± 9.2, and 90.9% were emergency hospital admissions. Patients were followed up for 1,417 ICU patient days, of which 396 days were in the early period and 1,021 days were in the late period. 7,354 RASS assessments were performed. Propofol and fentanyl were the sedative agents of choice in the early and late periods, respectively. Patients were mostly in the light sedation range, especially in the late period. At least one episode of delirium was seen in 23.7% of patients., Conclusion: Sedation practices in Singapore ICUs are characterised by light sedation depth and low incidence of delirium, possibly due to the drugs used., (Copyright: © Singapore Medical Association.)

Objectives: The Society of Critical Care Medicine recommends routine delirium monitoring, based on data in critically ill patients without primary neurologic injury. We sought to answer whether there are valid and reliable tools to monitor delirium in neurocritically ill patients and whether delirium is associated with relevant clinical outcomes (e.g., survival, length of stay, functional independence, cognition) in this population., Data Sources: We systematically reviewed Cumulative Index to Nursing and Allied Health Literature, Web of Science, and PubMed., Study Selection and Data Extraction: Inclusion criteria allowed any study design investigating delirium monitoring in neurocritically ill patients (e.g., neurotrauma, ischemic, and/or hemorrhagic stroke) of any age. We extracted data relevant to delirium tool sensitivity, specificity, negative predictive value, positive predictive value, interrater reliability, and associated clinical outcomes., Data Synthesis: Among seven prospective cohort studies and a total of 1,173 patients, delirium was assessed in neurocritically patients using validated delirium tools after considering primary neurologic diagnoses and associated complications, finding a pooled prevalence rate of 12-43%. When able to compare against a common reference standard, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the test characteristics showed a sensitivity of 62-76%, specificity of 74-98%, positive predictive value of 63-91%, negative predictive value of 70-94%, and reliability kappa of 0.64-0.94. Among four studies reporting multivariable analyses, delirium in neurocritically patients was associated with increased hospital length of stay (n = 3) and ICU length of stay (n = 1), as well as worse functional independence (n = 1) and cognition (n = 2), but not survival., Conclusions: These data from studies of neurocritically ill patients demonstrate that patients with primary neurologic diagnoses can meet diagnostic criteria for delirium and that delirious features may predict relevant untoward clinical outcomes. There is a need for ongoing investigations regarding delirium in these complicated neurocritically ill patients.

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.

Delirium, a prevalent organ dysfunction in critically ill patients, is independently associated with increased morbidity. This last decade has witnessed an exponential growth in delirium research in hospitalized patients, including those critically ill, and this research has highlighted that delirium needs to be better understood mechanistically to help foster research that will ultimately lead to its prevention and treatment. In this invited, evidence-based paper, a multinational and interprofessional group of clinicians and researchers from within the fields of critical care medicine, psychiatry, pediatrics, anesthesiology, geriatrics, surgery, neurology, nursing, pharmacy, and the neurosciences sought to address five questions: (1) What is the current standard of care in managing ICU delirium? (2) What have been the major recent advances in delirium research and care? (3) What are the common delirium beliefs that have been challenged by recent trials? (4) What are the remaining areas of uncertainty in delirium research? (5) What are some of the top study areas/trials to be done in the next 10 years? Herein, we briefly review the epidemiology of delirium, the current best practices for management of critically ill patients at risk for delirium or experiencing delirium, identify recent advances in our understanding of delirium as well as gaps in knowledge, and discuss research opportunities and barriers to implementation, with the goal of promoting an integrated research agenda.

Rationale: Choice and intensity of early (first 48 h) sedation may affect short- and long-term outcome., Objectives: To investigate the relationships between early sedation and time to extubation, delirium, and hospital and 180-day mortality among ventilated critically ill patients in the intensive care unit (ICU)., Methods: Multicenter (25 Australia and New Zealand hospitals) prospective longitudinal (ICU admission to 28 d) cohort study of medical/surgical patients ventilated and sedated 24 hours or more. We assessed administration of sedative agents, ventilation time, sedation depth using Richmond Agitation Sedation Scale (RASS, four hourly), delirium (daily), and hospital and 180-day mortality. We used multivariable Cox regression to quantify relationships between early deep sedation (RASS, -3 to -5) and patients' outcomes., Measurements and Main Results: We studied 251 patients (mean age, 61.7 ± 15.9 yr; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 20.8 ± 7.8), with 21.1% (53) hospital and 25.8% (64) 180-day mortality. Over 2,678 study days, we completed 14,736 RASS assessments. Deep sedation occurred in 191 (76.1%) patients within 4 hours of commencing ventilation and in 171 (68%) patients at 48 hours. Delirium occurred in 111 (50.7%) patients with median (interquartile range) duration of 2 (1-4) days. After adjusting for diagnosis, age, sex, APACHE II, operative, elective, hospital type, early use of vasopressors, and dialysis, early deep sedation was an independent predictor of time to extubation (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.94; P < 0.001), hospital death (HR, 1.11; 95% CI, 1.02-1.20; P = 0.01), and 180-day mortality (HR, 1.08; 95% CI, 1.01-1.16; P = 0.026) but not delirium occurring after 48 hours (P = 0.19)., Conclusions: Early sedation depth independently predicts delayed extubation and increased mortality, making it a potential target for interventional studies.

Objectives: To determine the relationship between the number of delirium days experienced by intensive care patients and mortality, ventilation time, and intensive care unit stay., Design: Prospective cohort analysis., Setting: Patients from 68 intensive care units in five countries., Patients: Three hundred fifty-four medical and surgical intensive care patients enrolled in the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial received a sedative study drug and completed at least one delirium assessment., Interventions: Sedative drug interruption and/or titration to maintain light sedation with daily arousal and delirium assessments up to 30 days of mechanical ventilation., Measurements and Main Results: The primary outcome was all-cause 30-day mortality. Multivariable analysis using Cox regression incorporating delirium duration as a time-dependent variable and adjusting for eight relevant baseline covariates was conducted to quantify the relationship between number of delirium days and the three main outcomes. Overall, delirium was diagnosed in 228 of 354 patients (64.4%). Mortality was significantly lower in patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%]; p<.001). Similarly, the median time to extubation and intensive care unit discharge were significantly shorter among nondelirious patients (3.6 vs. 10.7 days [p<.001] and 4 vs. 16 days [p<.001], respectively). In multivariable analysis, the duration of delirium exhibited a nonlinear relationship with mortality (p=.02), with the strongest association observed in the early days of delirium. In comparison to 0 days of delirium, an independent dose-response increase in mortality was observed, which increased from 1 day of delirium (hazard ratio, 1.70; 95% confidence interval, 1.27-2.29; p<.001), 2 days of delirium (hazard ratio, 2.69; confidence interval, 1.58-4.57; p<.001), and ≥3 days of delirium (hazard ratio, 3.37; confidence interval, 1.92-7.23; p<.001). Similar independent relationships were observed between delirium duration and ventilation time and intensive care length of stay., Conclusions: In ventilated and lightly sedated intensive care unit patients, the duration of delirium was the strongest independent predictor of death, ventilation time, and intensive care unit stay after adjusting for relevant covariates.

Background: Commonly used sedatives/analgesics can increase the risk of postoperative complications, including delirium. This double-blinded study assessed the neurobehavioral, hemodynamic, and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia., Methods: A total of 306 patients at least 60 yr old were randomized to receive dexmedetomidine (0.1-0.7 microg x kg(-1) x h(-1)) or morphine (10-70 microg x kg(-1) x h(-1)) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2-4. Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care. Secondary outcomes included ventilation time, additional sedation/analgesia, and hemodynamic and adverse effects., Results: Of all sedation assessments, 75.2% of dexmedetomidine and 79.6% (P = 0.516) of morphine treatment were in the target range. Delirium incidence was comparable between dexmedetomidine 13 (8.6%) and morphine 22 (15.0%) (relative risk 0.571, 95% confidence interval [CI] 0.256-1.099, P = 0.088), however, dexmedetomidine-managed patients spent 3 fewer days (2 [1-7] versus 5 [2-12]) in delirium (95% CI 1.09-6.67, P = 0.0317). The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine (3 of 20 [15%] versus 9 of 25 [36%]) (relative risk 0.416, 95% CI 0.152-0.637, P = 0.001). Dexmedetomidine-treated patients were more likely to be extubated earlier (relative risk 1.27, 95% CI 1.01-1.60, P = 0.040, log-rank P = 0.036), experienced less systolic hypotension (23% versus 38.1%, P = 0.006), required less norepinephrine (P < 0.001), but had more bradycardia (16.45% versus 6.12%, P = 0.006) than morphine treatment., Conclusion: Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation, less hypotension, less vasopressor requirement, and more bradycardia versus morphine regimen.

A survey was conducted to determine sedation and delirium practices in Australian and New Zealand intensive care units. The survey was in two parts, comprising an online survey of reported sedation and delirium management (unit survey) and a collection of de-identified data about each patient in a unit at a given time on a specified day (patient snapshot survey). All intensive care units throughout Australia and New Zealand were invited by email to participate in the survey. Twenty-three predominantly metropolitan, level III Australian and New Zealand intensive care units treating adult patients participated. Written sedation policies were in place in 48% of units, while an additional 44% of units reported having informal sedation policies. Seventy percent of units routinely used a sedation scale. In contrast, only 9% of units routinely used a delirium scale. Continuous intravenous infusion is the primary means of patient sedation (74% of units). While 30% of units reported routinely interrupting sedation, only 10% of sedated patients in the snapshot survey had had their sedation interrupted in the preceding 12 hours. Oversedation appears to be common (46% of patients with completed sedation scales). Use of neuromuscular blockade is low (10%) compared to other published studies. Midazolam and propofol were the most frequently used sedatives. The proportion of patients developing delirium was 21% of assessable patients. Failed and self-extubation rates were low: 3.2% and 0.5% respectively. In Australian and New Zealand intensive care units, routine use of sedation scales is common but not universal, while routine delirium assessment is rare. The use of a sedation protocol is valuable and should be encouraged.

BACKGROUND Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied. METHODS In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 [unresponsive] to +4 [combative]) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days. RESULTS We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group. CONCLUSIONS Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.) [ABSTRACT FROM AUTHOR]