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Delirium is the most common manifestation of brain dysfunction in critically ill patients. In the intensive care unit (ICU), duration of delirium is independently predictive of excess death, length of stay, cost of care, and acquired dementia. There are numerous neurotransmitter/functional and/or injury-causing hypotheses rather than a unifying mechanism for delirium. Without using a validated delirium instrument, delirium can be misdiagnosed (under, but also overdiagnosed and trivialized), supporting the recommendation to use a monitoring instrument routinely. The best-validated ICU bedside instruments are CAM-ICU and ICDSC, both of which also detect subsyndromal delirium. Both tools have some inherent limitations in the neurologically injured patients, yet still provide valuable information about delirium once the sequelae of the primary injury settle into a new post-injury baseline. Now it is known that antipsychotics and other psychoactive medications do not reliably improve brain function in critically ill delirious patients. ICU teams should systematically screen for predisposing and precipitating factors. These include exacerbations of cardiac/respiratory failure or sepsis, metabolic disturbances (hypoglycemia, dysnatremia, uremia and ammonemia) receipt of psychoactive medications, and sensory deprivation through prolonged immobilization, uncorrected vision and hearing deficits, poor sleep hygiene, and isolation from loved ones so common during COVID-19 pandemic. The ABCDEF (A2F) bundle is a means to facilitate implementation of the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) Guidelines. In over 25,000 patients across nearly 100 institutions, the A2F bundle has been shown in a dose–response fashion (i.e., greater bundle compliance) to yield improved survival, length of stay, coma and delirium duration, cost, and less ICU bounce-backs and discharge to nursing homes.

In a multicenter trial in 566 patients with critical illness who had delirium, the use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the duration of delirium or coma. Side effects and extrapyramidal disorders occurred at similar rates in all groups.

RATIONALE:Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown. OBJECTIVES:To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death. RESEARCH DESIGN:We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center. SUBJECTS:We analyzed critically ill patients (N=479) with respiratory failure and/or shock. MEASURES:Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression methodfirst, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium’s association with early mortality in the ICU. RESULTS:The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132–$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056–7869). CONCLUSIONS:Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.

The prevalence of frailty (diminished physiologic reserve) and its effect on outcomes for those aged 18 years and older with critical illness is unclear. We hypothesized greater frailty would be associated with subsequent mortality, disability, and cognitive impairment, regardless of age. At enrollment, we measured frailty using the Clinical Frailty Scale (range, 1 [very fit] to 7 [severely frail]). At 3 and 12 months post-discharge, we assessed vital status, instrumental activities of daily living, basic activities of daily living, and cognition. We used multivariable regression to analyze associations between Clinical Frailty Scale scores and outcomes, adjusting for age, sex, education, comorbidities, baseline disability, baseline cognition, severity of illness, delirium, coma, sepsis, mechanical ventilation, and sedatives/opiates. We enrolled 1,040 patients who were a median (interquartile range) of 62 (53-72) years old and who had a median Clinical Frailty Scale score of 3 (3-5). Half of those with clinical frailty (i.e., Clinical Frailty Scale score ≥5) were younger than 65 years old. Greater Clinical Frailty Scale scores were independently associated with greater mortality (P = 0.01 at 3 mo and P < 0.001 at 12 mo) and with greater odds of disability in instrumental activities of daily living (P = 0.04 at 3 mo and P = 0.002 at 12 mo). Clinical Frailty Scale scores were not associated with disability in basic activities of daily living or with cognition. Frailty is common in critically ill adults aged 18 years and older and is independently associated with increased mortality and greater disability. Future studies should explore routine screening for clinical frailty in critically ill patients of all ages. Interventions to reduce mortality and disability among patients with heightened vulnerability should be developed and tested. Clinical trial registered with www.clinicaltrials.gov (NCT 00392795 and NCT 00400062).

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.

Objective To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). Background Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. Methods This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. Results Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p  = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p  = 0.012), there were no between-group differences in the secondary outcomes. Conclusion Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

The agent that should be used for light sedation of patients requiring mechanical ventilation is unclear. This randomized trial compared dexmedetomidine with propofol for the light sedation of critically ill patients with sepsis who required mechanical ventilation. No clinically important differences were found.

Background Antipsychotics are used to treat delirium in the intensive care unit (ICU) despite unproven efficacy. We hypothesized that atypical antipsychotic treatment in the ICU is a risk factor for antipsychotic prescription at discharge, a practice that might increase risk since long-term use is associated with increased mortality. Methods After excluding patients on antipsychotics prior to admission, we examined antipsychotic use in a prospective cohort of ICU patients with acute respiratory failure and/or shock. We collected data on medication use from medical records and assessed patients for delirium using the Confusion Assessment Method for the ICU. Using multivariable logistic regression, we analyzed whether age, delirium duration, atypical antipsychotic use, and discharge disposition (each selected a priori) were independent risk factors for discharge on an antipsychotic. We also examined admission Acute Physiology and Chronic Health Evaluation (APACHE) II score, haloperidol use, and days of benzodiazepine use in post hoc analyses. Results After excluding 18 patients due to prior antipsychotic use and three who withdrew, we included 500 patients. Among 208 (42%) treated with an antipsychotic, median (interquartile range) age was 59 (49–69) years and APACHE II score was 26 (22–32), characteristics that were similar among antipsychotic nonusers. Antipsychotic users were more likely than nonusers to have had delirium (93% vs. 61%, p  < 0.001). Of the 208 antipsychotic users, 172 survived to hospital discharge, and 42 (24%) of these were prescribed an antipsychotic at discharge. Treatment with an atypical antipsychotic was the only independent risk factor for antipsychotic prescription at discharge (odds ratio 17.6, 95% confidence interval 4.9 to 63.3; p  < 0.001). Neither age, delirium duration, nor discharge disposition were risk factors ( p  = 0.11, 0.38, and 0.12, respectively) in the primary regression model, and post hoc analyses found APACHE II ( p  = 0.07), haloperidol use ( p  = 0.16), and days of benzodiazepine use ( p  = 0.31) were also not risk factors for discharge on an antipsychotic. Conclusions In this study, antipsychotics were used to treat nearly half of all antipsychotic-naïve ICU patients and were prescribed at discharge to 24% of antipsychotic-treated patients. Treatment with an atypical antipsychotic greatly increased the odds of discharge with an antipsychotic prescription, a practice that should be examined carefully during medication reconciliation since these drugs carry “black box warnings” regarding long-term use.

Conventional gabaminergic sedatives such as benzodiazepines and propofol are commonly used in mechanically ventilated patients in the intensive care unit (ICU). Dexmedetomidine is an alternative sedative that may achieve lighter sedation, reduce delirium, and provide analgesia. Our objective was to perform a comprehensive systematic review summarizing the large body of evidence, determining if dexmedetomidine reduces delirium compared to conventional sedatives. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and the WHO ICTRP from inception to October 2021. Independent pairs of reviewers identified randomized clinical trials comparing dexmedetomidine to other sedatives for mechanically ventilated adults in the ICU. We conducted meta-analyses using random-effects models. The results were reported as relative risks (RRs) for binary outcomes and mean differences (MDs) for continuous outcomes, with corresponding 95% confidence intervals (CIs). In total, 77 randomized trials (n = 11,997) were included. Compared to other sedatives, dexmedetomidine reduced the risk of delirium (RR 0.67, 95% CI 0.55 to 0.81; moderate certainty), the duration of mechanical ventilation (MD − 1.8 h, 95% CI  – 2.89 to  – 0.71; low certainty), and ICU length of stay (MD  – 0.32 days, 95% CI  – 0.42 to  – 0.22; low certainty). Dexmedetomidine use increased the risk of bradycardia (RR 2.39, 95% CI 1.82 to 3.13; moderate certainty) and hypotension (RR 1.32, 95% CI 1.07 to 1.63; low certainty). In mechanically ventilated adults, the use of dexmedetomidine compared to other sedatives, resulted in a lower risk of delirium, and a modest reduction in duration of mechanical ventilation and ICU stay, but increased the risks of bradycardia and hypotension.

Background Delirium is a frequent manifestation of acute brain dysfunction and is associated with cognitive impairment. The hypothesized mechanism of brain dysfunction during critical illness is centered on neuroinflammation, regulated in part by the cholinergic system. Point-of-care serum cholinesterase enzyme activity measurements serve as a real-time index of cholinergic activity. We hypothesized that cholinesterase activity during critical illness would be associated with delirium in the intensive care unit (ICU) and cognitive impairment after discharge. Methods We enrolled adults with respiratory failure and/or shock and measured plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity on days 1, 3, 5, and 7 after enrollment. AChE values were also normalized per gram of hemoglobin (AChE/Hgb). We assessed for coma and delirium twice daily using the Richmond Agitation Sedation Scale and the Confusion Assessment Method for the ICU to evaluate daily mental status (delirium, coma, normal) and days alive without delirium or coma. Cognitive impairment, disability, and health-related quality of life were assessed at up to 6 months post-discharge. We used multivariable regression to determine whether AChE, AChE/Hgb, and BChE activity were associated with outcomes after adjusting for relevant covariates. Results We included 272 critically ill patients who were a median (IQR) age 56 (39–67) years and had a median Sequential Organ Failure Assessment score at enrollment of 8 (5–11). Higher daily AChE levels were associated with increased odds of being delirious versus normal mental status on the same day (Odds Ratio [95% Confidence Interval] 1.64 [1.11, 2.43]; P  = 0.045). AChE/Hgb and BChE activity levels were not associated with delirious mental status. Lower enrollment BChE was associated with fewer days alive without delirium or coma ( P  = 0.048). AChE, AChE/Hgb, and BChE levels were not significantly associated with cognitive impairment, disability, or quality of life after discharge. Conclusion Cholinesterase activity during critical illness is associated with delirium but not with outcomes after discharge, findings that may reflect mechanisms of acute brain organ dysfunction. Trial Registration: NCT03098472. Registered 31 March 2017.