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Objectives: Sepsis survivors have greater healthcare use than those surviving hospitalizations for other reasons, yet factors associated with greater healthcare use in this population remain ill-defined. Rural Americans are older, have more chronic illnesses, and face unique barriers to healthcare access, which could affect postsepsis healthcare use. Therefore, we compared healthcare use and expenditures among rural and urban sepsis survivors. We hypothesized that rural survivors would have greater healthcare use and expenditures., Design, Setting, and Patients: To test this hypothesis, we used data from 106,189 adult survivors of a sepsis hospitalization included in the IBM MarketScan Commercial Claims and Encounters database and Medicare Supplemental database between 2013 and 2018., Interventions: None., Measurements and Main Results: We identified hospitalizations for severe sepsis and septic shock using the International Classification of Diseases , 9th Edition (ICD-9) or 1CD-10 codes. We used Metropolitan Statistical Area classifications to categorize rurality. We measured emergency department (ED) visits, inpatient hospitalizations, skilled nursing facility admissions, primary care visits, physical therapy visits, occupational therapy visits, and home healthcare visits for the year following sepsis hospitalizations. We calculated the total expenditures for each of these categories. We compared outcomes between rural and urban patients using multivariable regression and adjusted for covariates. After adjusting for age, sex, comorbidities, admission type, insurance type, U.S. Census Bureau region, employment status, and sepsis severity, those living in rural areas had 17% greater odds of having an ED visit (odds ratio [OR] 1.17; 95% CI, 1.13-1.22; p < 0.001), 9% lower odds of having a primary care visit (OR 0.91; 95% CI, 0.87-0.94; p < 0.001), and 12% lower odds of receiving home healthcare (OR 0.88; 95% CI, 0.84-0.93; p < 0.001). Despite higher levels of ED use and equivalent levels of hospital readmissions, expenditures in these areas were 14% (OR 0.86; 95% CI, 0.80-0.91; p < 0.001) and 9% (OR 0.91; 95% CI, 0.87-0.96; p < 0.001) lower among rural survivors, respectively, suggesting these services may be used for lower-acuity conditions., Conclusions: In this large cohort study, we report important differences in healthcare use and expenditures between rural and urban sepsis survivors. Future research and policy work is needed to understand how best to optimize sepsis survivorship across the urban-rural continuum., Competing Interests: Dr. Stinehart’s institution received funding from the National Institutes of Health (NIH) (K76AG054864, 1UM1TR004548). Mr. Hyer and Dr. Brummel received support for article research from the NIH. Dr. Brummel’s institution received funding from the NIH under award number K76AG054864. Mr. Joshi has disclosed that he does not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Early neuromuscular blockade with cisatracurium has been associated with improved outcomes in moderate-severe acute respiratory distress syndrome (ARDS). Previous studies have demonstrated increased drug utilization without benefits in oxygenation using fixed dose cisatracurium compared to train-of-four (TOF) titration. Objective: We sought to compare a novel, lower fixed dose cisatracurium protocol to TOF titration evaluating the impact on PaO2:FiO2 ratio (P/F). Methods: We conducted a single-center retrospective cohort study comparing fixed dose cisatracurium to TOF titration. We included patients aged 18-89 treated for COVID-19 ARDS with a baseline P/F≤200 who received a cisatracurium infusion for ≥12 h. The primary outcome was change in P/F at 48 h from baseline. Secondary outcomes included change in P/F at 24 h and 7 days, need for mechanical ventilation at day 28, and cisatracurium utilization. Results: Analyses included 125 patients (fixed dose = 65, TOF = 60). Severe ARDS was common with a baseline median P/F of 73.7 vs 79.5, P = .133. The change in P/F at 48 h was larger in the TOF cohort in the adjusted analysis (24.9 vs 70.8, P < .005). The rate and total cumulative dose of cisatracurium were higher in the fixed dose cohort (5 vs 3 mcg/kg/min, P < .001; 1034 vs 612 mg, P < .001) despite similar infusion durations (44.1 h vs 48.5 h, P = .642). Conclusions: Patients in the TOF cisatracurium cohort had improved P/F at 48 h compared to the fixed dose cohort, while also using only 60% of the cumulative dose. Future directions should include analysis of the implications of increased cisatracurium exposure on patient outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose of Review: In the decade since the first publications related to frailty in those with critical illness, the study of frailty has rapidly increased. The purpose of this review is to update the reader on recent advances across several important areas of frailty research: how best to identify frailty in those with critical illness, studies describing the relationship between frailty and delirium, and how frailty affects outcomes for those with coronavirus disease 2019 (COVID-19), which, despite rates and severity of acute infection declining, still tremendously impacts patients long after the acute infection, resulting in symptoms of long COVID-19., Recent Findings: A number of frailty assessment tools exist, to date, the Clinical Frailty Scale based on the deficit accumulation approach to defining frailty, is the most commonly used in ICU studies. Several novel frailty instruments for the ICU are being developed. Because tools assessing frailty by the phenotypic and deficit accumulation approaches identify different populations, careful choice of a frailty assessment tool is warranted.Frailty and delirium are hypothesized to represent different clinical expressions of a similar underlying vulnerability, thus identifying frailty may be a useful means by which to identify patients at high risk of becoming delirious. Recent studies show that frailty at ICU admission is a predictor of the development of delirium.Finally, frailty and its outcomes were studied in patients with COVID-19. As with other causes of critical illness, frailty was highly prevalent in those admitted to the ICU and is associated with greater mortality. Frailty was also associated with increased decisions to limit life support treatments, but these decisions were not different among those admitted with COVID-19 or for other reasons., Summary: Frailty in those with critical illness is an emerging field of study. Future work to define the optimal means by which to identify this syndrome and how best to manage critically ill patients with frailty are needed., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To date, age, frailty, and multimorbidity have been used primarily to inform prognosis in older adults. It remains uncertain, however, whether these patient factors may also predict response to critical care interventions or treatment outcomes., Data Sources: We conducted a systematic search of top general medicine and critical care journals for randomized controlled trials (RCTs) examining critical care interventions published between January 1, 2011, and December 31, 2021., Study Selection: We included RCTs of critical care interventions that examined any one of three subgroups-age, frailty, or multimorbidity. We excluded cluster RCTs, studies that did not report interventions in an ICU, and studies that did not report data examining subgroups of age, frailty, or multimorbidity., Data Extraction: We collected study characteristics (single vs. multicountry enrollment, single vs. multicenter enrollment, funding, sample size, intervention, comparator, primary outcome and secondary outcomes, length of follow-up), study population (inclusion and exclusion criteria, average age in intervention and comparator groups), and subgroup data. We used the Instrument for assessing the Credibility of Effect Modification Analyses instrument to evaluate the credibility of subgroup findings., Data Synthesis: Of 2037 unique citations, we included 48 RCTs comprising 50,779 total participants. Seven (14.6%) RCTs found evidence of statistically significant effect modification based on age, whereas none of the multimorbidity or frailty subgroups found evidence of statistically significant subgroup effect. Subgroup credibility ranged from very low to moderate., Conclusions: Most critical care RCTs do not examine for subgroup effects by frailty or multimorbidity. Although age is more commonly considered, the cut-point is variable, and relative effect modification is rare. Although interventional effects are likely similar across age groups, shared decision-making based on individual patient preferences must remain a priority. RCTs focused specifically on critically ill older adults or those living with frailty and/or multimorbidity are crucial to further address this research question., Competing Interests: Dr. Geen received funding from Outro Health. Dr. Ferrante’s institution received funding from the National Institutes of Health (NIH). Dr. Ferrante is supported by a Paul B. Beeson Emerging Leaders in Aging Career Development Award from the National Institute on Aging (K76 AG057203) and the Yale Claude D. Pepper Older Americans Independence Center (P30 AG021342). Drs. Ferrante and Brummel received support for article research from the NIH. Dr. Brummel’s institution received funding from the National Institute on Aging. Dr. Muscedere is the Scientific Director of the Canadian Frailty Network, which is funded by the Government of Canada. Dr. Brummel is supported by the National Institutes of Health under awards R01HD107103 and R01AG077644. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes., Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete., Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo., Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults., Funding: National Institutes of Health and the US Department of Veterans Affairs., Competing Interests: Declaration of interests The following declarations of interest are reported outside of the submitted work. MFM reports grants from the National Institutes of Health (NIH) and the US Department of Veterans Affairs. LMB reports grants from the NIH and the American Association of Critical Care Nurses. MNG reports grants from the NIH, the Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention; consulting fees for a role as scientific advisor for Endpoint Health; honoraria for grand rounds presentation at Yale University (New Haven, CT, USA); travel support from the American Thoracic Society executive committee; and participation on the data safety monitoring board for a trial on monoclonal antibodies for COVID-19, funded by Regeneron (NCT04452318). AM reports consulting fees from Zoll, Eli Lilly, LivaNova, and Jazz Pharmaceuticals; and a philanthropic contribution from ResMed to the University of California San Diego (La Jolla, CA, USA). BAK reports grants from the NIH, payment for expert testimony for a medicolegal case in the state of Indiana (USA), payment for participation on a data safety monitoring board for the PANDORA trial, and a leadership role as president of the American Delirium Society. SSC reports grants from the NIH and direct payments for participation on the data safety monitoring board of an NIH-funded study unrelated to delirium. CLH reports grants from the NIH. PR reports grants from the NIH and the US Department of Defense, payment and travel support for a continuing medical education event at the Johns Hopkins School of Medicine, and previous leadership of the Association of Academic Anesthesiology Chairs and Society of Academic Associations of Anesthesiology and Perioperative Medicine. BTP reports leadership as co-chair of the Society of Critical Care Medicine ICU Liberation Committee. PPP reports grants from the NIH. NEB reports grants from the NIH and travel support for the Society of Intensive Care Medicine Singapore annual meeting. CGH reports consulting fees for Sedana Medical. MBP reports grants from CSL Behring, the NIH, and the US Department of Defense; royalties for serving as an associate editor with Elsevier on a surgical textbook; travel support for continuing medical education events with the Eastern Association for the Surgery of Trauma, Society of University Surgeons, and American College of Surgeons; a patent for image-derived prognostic models unrelated to this work; participation on a data safety monitoring board for Liberate Medical; and leadership as treasurer for the Eastern Association for the Surgery of Trauma. JLS reports honoria for presentations for the Society of Critical Care Medicine, American College of Chest Physicians, the Chilean Society of Critical Care Medicine, and the Spanish Society of Hospital Pharmacy; travel support for meetings with the Society of Critical Care Medicine, the Saudi Society of Clinical Pharmacy, and the Chilean Society of Critical Care Medicine; and leadership on committees with the Society of Critical Care Medicine. EWE reports grant support from the NIH and the US Department of Veterans Affairs, honoraria for continuing medical education lectures sponsored by Pfizer, and study support (investigational drug provision, no direct payments) from Eli Lilly. TDG reports grants from the NIH, research funding from Ceribell, and personal fees from Haisco Pharmaceutical and Lungpacer Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness., Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives., Results: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status., Conclusion: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology., Methods: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts., Results: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations., Discussion: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes., Highlights: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Catatonia, a form of acute brain dysfunction typically linked with severe affective and psychotic disorders, occurs in critical illness with delirium and coma. Delirium and coma are associated with mortality, though catatonia's relationship with mortality is unclear. We aim to describe whether catatonia, delirium, and coma are associated with mortality., Methods: We enrolled a convenience cohort of critically ill adults (N = 378) at an academic medical center. We assessed catatonia, delirium, and coma using the Bush-Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale, respectively. We tested the associations between previous day brain dysfunction state occurrence with in-hospital and one-year mortality using multivariable time-dependent risk models. Additionally, we tested the association between brain dysfunction duration and one-year mortality., Results: Catatonia was not associated with death on the day after diagnosis during hospitalization, and neither previous catatonia occurrence nor duration was associated with one-year mortality. Delirium was not associated with death on any day following diagnosis during hospitalization, and neither previous delirium occurrence nor duration was associated with one-year mortality. The occurrence of coma was associated with death on any day after diagnosis during hospitalization (HR 2.30,CI 1.19-4.44,p = 0.014), as well as through one year following hospital discharge (HR 1.68,CI 1.09-2.59,p = 0.02)., Conclusions: Coma, but neither catatonia nor delirium, was associated with future day in-hospital and one-year mortality. More research is needed to understand catatonia's clinical impact. Delirium results differ from existing literature likely due to cohort demographics and size. Coma results highlight the prognostic significance of suppressed arousal while critically ill., Competing Interests: Declaration of competing interest The authors disclose that the research was conducted in the absence of any commercial or financial relationships that could be seen as a potential conflict of interest., (Published by Elsevier B.V.)

People with respiratory disease have increased risk of developing frailty, which is associated with worse health outcomes. There is growing evidence of the role of rehabilitation in managing frailty in people with respiratory disease. However, several challenges remain regarding optimal methods of identifying frailty and delivering rehabilitation for this population. The aims of this American Thoracic Society workshop were to outline key definitions and concepts around rehabilitation for people with respiratory disease and frailty, synthesize available evidence, and explore how programs may be adapted to align to the needs and experiences of this population. Across two half-day virtual workshops, 20 professionals from diverse disciplines, professions, and countries discussed key developments and identified opportunities for future research, with additional input via online correspondence. Participants highlighted a "frailty rehabilitation paradox" whereby pulmonary rehabilitation can effectively reduce frailty, but programs are challenging for some individuals with frailty to complete. Frailty should not limit access to rehabilitation; instead, the identification of frailty should prompt comprehensive assessment and tailored support, including onward referral for additional specialist input. Exercise prescriptions that explicitly consider symptom burden and comorbidities, integration of additional geriatric or palliative care expertise, and/or preemptive planning for disruptions to participation may support engagement and outcomes. To identify and measure frailty in people with respiratory disease, tools should be selected on the basis of sensitivity, specificity, responsiveness, and feasibility for their intended purpose. Research is required to expand understanding beyond the physical dimensions of frailty and to explore the merits and limitations of telerehabilitation or home-based pulmonary rehabilitation for people with chronic respiratory disease and frailty.

Objective: To identify quantitative electroencephalography (EEG)-based indicators of delirium or coma in mechanically ventilated patients., Methods: We prospectively enrolled 28 mechanically ventilated intensive care unit (ICU) patients to undergo 24-hour continuous EEG, 25 of whom completed the study. We assessed patients twice daily using the Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU). We evaluated the spectral profile, regional connectivity and complexity of 5-minute EEG segments after each assessment. We used penalized regression to select EEG metrics associated with delirium or coma, and compared mixed-effects models predicting delirium with and without the selected EEG metrics., Results: Delta variability, high-beta variability, relative theta power, and relative alpha power contributed independently to EEG-based identification of delirium or coma. A model with these metrics achieved better prediction of delirium or coma than a model with clinical variables alone (Akaike Information Criterion: 36 vs 43, p = 0.006 by likelihood ratio test). The area under the receiver operating characteristic curve for an ad hoc hypothetical delirium score using these metrics was 0.94 (95%CI 0.83-0.99)., Conclusions: We identified four EEG metrics that, in combination, provided excellent discrimination between delirious/comatose and non-delirious mechanically ventilated ICU patients., Significance: Our findings give insight to neurophysiologic changes underlying delirium and provide a basis for pragmatic, EEG-based delirium monitoring technology., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s).)

Objectives: Among critically ill patients, acutely depressed level of consciousness is associated with mortality, but its relationship to long-term outcomes such as disability and physical function is unknown. We investigated the relationship of level of consciousness during hospitalization with long-term disability and physical function in ICU survivors., Design: Multi-center observational cohort study., Setting: Medical or surgical ICUs at five U.S. centers., Patients: Adult survivors of respiratory failure or shock., Interventions: None., Measurements and Main Results: Depressed level of consciousness during hospitalization was defined using the Richmond Agitation Sedation Scale (RASS) score (including all negative scores) by calculating the area under the curve using linear interpolation. Sedative-associated level of consciousness was similarly defined for all hospital days that sedation was received. We measured disability in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), discharge destination, and self-reported physical function. In separate models, we evaluated associations between these measures of level of consciousness and outcomes using multivariable regression, adjusted for age, sex, race, body mass index, education level, comorbidities, baseline frailty, baseline IADLs and BADLs, hospital type (civilian vs veteran), modified mean daily Sequential Organ Failure Assessment score, duration of severe sepsis, duration of mechanical ventilation, and hospital length of stay. Of the 1,040 patients enrolled in the ICU, 781 survived to hospital discharge. We assessed outcomes in 624 patients at 3 months and 527 patients at 12 months. After adjusting for covariates, there was no association between depressed level of consciousness (total or sedation-associated) with BADLs or IADLs at either 3- or 12-month follow-up. There was also no association with self-reported physical function at 3 or 12 months or with discharge destination., Conclusions: Depressed level of consciousness, as defined by the RASS, was not associated with disability or self-reported physical function. Future studies should investigate additional modifiable in-hospital risk factors for disability and poor physical function following critical illness., Competing Interests: Dr. Mart’s institution received funding from the National Institute on Aging (R01AG027472 and R01AG035117), Veterans Affairs (VA) Merit Award, and the National Heart, Lung, and Blood Institute (T32HL08773814). Drs. Mart, Ely, Pandharipande, Patel, Roberson, and Brummel received support for article research from the National Institutes of Health (NIH). Drs. Patel’s, Roberson’s, and Brummel’s institutions received funding from the NIH. Dr. Patel’s institution received funding from the Department of Defense; he received funding from the Eastern Association for the Surgery of Trauma Board of Directors, the NIH Center for Scientific Review Surgery, Anesthesiology, and Trauma study section, Haemonetics Research Device Support, and Liberate Medical Scientific Advisory Board. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: ICU survivors suffer from impaired physical function and reduced exercise capacity, yet the underlying mechanisms are poorly understood. The goal of this exploratory pilot study was to investigate potential mechanisms of exercise limitation using cardiopulmonary exercise testing (CPET) and 6-min walk testing (6MWT)., Methods: We enrolled adults aged 18 years or older who were treated for respiratory failure or shock in medical, surgical, or trauma ICUs at Vanderbilt University Medical Center (Nashville, TN, United States). We excluded patients with pre-existing cardiac dysfunction, a contraindication to CPET, or the need for supplemental oxygen at rest. We performed CPET and 6MWT 6 months after ICU discharge. We measured standard CPET parameters in addition to two measures of oxygen utilization during exercise (VO 2 -work rate slope and VO 2 recovery half-time)., Results: We recruited 14 participants. Low exercise capacity (i.e., VO 2Peak  < 80% predicted) was present in 11 out of 14 (79%) with a median VO 2Peak of 12.6 ml/kg/min [9.6-15.1] and 6MWT distance of 294 m [240-433]. In addition to low VO 2Peak , CPET findings in survivors included low oxygen uptake efficiency slope, low oxygen pulse, elevated chronotropic index, low VO 2 -work rate slope, and prolonged VO 2 recovery half-time, indicating impaired oxygen utilization with a hyperdynamic heart rate and ventilatory response, a pattern seen in non-critically ill patients with mitochondrial myopathies. Worse VO 2 -work rate slope and VO 2 recovery half-time were strongly correlated with worse VO 2Peak and 6MWT distance, suggesting that exercise capacity was potentially limited by impaired muscle oxygen utilization., Conclusions: These exploratory data suggest ICU survivors may suffer from impaired muscular oxygen metabolism due to mitochondrial dysfunction that impairs exercise capacity long-term. These findings should be further characterized in future studies that include direct assessments of muscle mitochondrial function in ICU survivors., (© 2022. The Author(s).)

Introduction: Catatonia, characterized by motor, behavioral and affective abnormalities, frequently co-occurs with delirium during critical illness. Advanced age is a known risk factor for development of delirium. However, the association between age and catatonia has not been described. We aim to describe the occurrence of catatonia, delirium, and coma by age group in a critically ill, adult population. Design: Convenience cohort, nested within two clinical trials and two observational cohort studies. Setting: Intensive care units in an academic medical center in Nashville, TN. Patients: 378 critically ill adult patients on mechanical ventilation and/or vasopressors. Measurements and Main Results: Patients were assessed for catatonia, delirium, and coma by independent and blinded personnel, the Bush Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit (ICU) and the Richmond Agitation and Sedation Scale. Of 378 patients, 23% met diagnostic criteria for catatonia, 66% experienced delirium, and 52% experienced coma during the period of observation. There was no relationship found between age and catatonia severity or age and presence of specific catatonia items. The prevalence of catatonia was strongly associated with age in the setting of critical illness ( p < 0.05). Delirium and comas' association with age was limited to the setting of catatonia. Conclusion: Given the significant relationship between age and catatonia independent of coma and delirium status, these data demonstrate catatonia's association with advanced age in the setting of critical illness. Future studies can explore the causative factors for this association and further elucidate the risk factors for acute brain dysfunction across the age spectrum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Connell, Kim, Brummel, Patel, Vandekar, Pandharipande, Dittus, Heckers, Ely and Wilson.)

Background: The temporal association of delirium during critical illness with mortality is unclear, along with the associations of hypoactive and hyperactive motoric subtypes of delirium with mortality. We aimed to evaluate the relationship of delirium during critical illness, including hypoactive and hyperactive motoric subtypes, with mortality in the hospital and after discharge up to 1 year., Methods: We analyzed a prospective cohort study of adults with respiratory failure and/or shock admitted to university, community, and Veterans Affairs hospitals. We assessed patients using the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the intensive care unit (ICU) and defined the motoric subtype according to the corresponding Richmond Agitation-Sedation Scale if delirium was present. We used Cox proportional hazard models, adjusted for baseline characteristics, coma, and daily hospital events, to determine whether delirium on a given day predicted mortality the following day in patients in the hospital and also to determine whether delirium presence and duration predicted mortality after discharge up to 1 year in patients who survived to hospital discharge. We performed similar analyses for hypoactive and hyperactive subtypes of delirium., Results: Among 1040 critically ill patients, 214 (21%) died in the hospital and 204 (20%) died out-of-hospital by 1 year. Delirium was common, occurring in 740 (71%) patients for a median (interquartile range [IQR]) of 4 (2-7) days. Hypoactive delirium occurred in 733 (70%) patients, and hyperactive occurred in 185 (18%) patients, with a median (IQR) of 3 (2-7) days and 1 (1-2) days, respectively. Delirium on a given day (hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.32-6.21; P = .008), in particular the hypoactive subtype (HR, 3.35; 95% CI, 1.51-7.46; P = .003), was independently associated with an increased risk of death the following day in the hospital. Hyperactive delirium was not associated with an increased risk of death in the hospital (HR, 4.00; 95% CI, 0.49-32.51; P = .19). Among hospital survivors, neither delirium presence (HR, 1.01; 95% CI, 0.82-1.24; P = .95) nor duration (HR, 0.99; 95% CI, 0.97-1.01; P = .56), regardless of motoric subtype, was associated with mortality after hospital discharge up to 1 year., Conclusions: Delirium during critical illness is associated with nearly a 3-fold increased risk of death the following day for patients in the hospital but is not associated with mortality after hospital discharge. This finding appears primarily driven by the hypoactive motoric subtype. The independent relationship between delirium and mortality occurs early during critical illness but does not persist after hospital discharge., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Background and Aims: Risk factors for poor outcomes after critical illness are incompletely understood. While nutritional risk is associated with mortality in critically ill patients, its association with disability, cognitive, and health-related quality of life is unclear in survivors of critical illness. This study's objective was to determine whether greater nutritional risk at ICU admission is associated with greater disability, worse cognition, and worse HRQOL at 3 and 12-month follow-up., Methods: We enrolled adults (≥18 years of age) with respiratory failure or shock treated in medical and surgical intensive care units from two U.S. centers. We measured nutritional risk using the modified Nutrition Risk in Critically Ill (mNUTRIC) score (range 0-9 [highest risk]) at intensive care unit admission. We measured associations between mNUTRIC scores and discharge destination, disability in basic activities of daily living (ADLs) using the Katz ADL, instrumental ADLs using the Functional Activities Questionnaire (FAQ), global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), executive function using the Trail Making Test Part B (Trails B), and health-related quality of life using the SF-36, adjusting for sex, education, BMI, baseline frailty, disability, and cognition, severity of illness, days of delirium, coma, and mechanical ventilation., Results: Of the 821 patients enrolled in the ICU, 636 patients survived to hospital discharge. We assessed outcomes in 448 of 535 survivors (84%) at 3 months and 382 of 476 survivors (80%) at 12 months. Higher mNUTRIC scores predicted greater odds of discharge to an institution (OR 2.0, 95% CI: 1.6 to 2.6; P < 0.01). Higher mNUTRIC scores were associated with a trend towards greater disability in basic activities of daily living (IRR 1.3, 95% CI 1.0 to 1.7) at 3 months that did not reach significance (p = 0.09) with no association demonstrated at 12 months. There were no associations between mNUTRIC scores and FAQ, RBANS, or Trails B scores. mNUTRIC scores were inconsistently associated with SF-36 physical and mental component scale scores., Conclusions: Greater nutritional risk at ICU admission is associated with disability in survivors of critical illness. Future studies should evaluate interventions in those at high nutritional risk as a means to speed recovery., Competing Interests: Conflicts of interest Dr. Mart received grant funding through the Vanderbilt University Medical Center Arthur and Lisa Wheeler Critical Care Research grant and research training support from the National Institutes of Health, under award number T32HL087738. Dr. Girard received grant funding from the NIH under award numbers R01AG035117 and R01HL135144. Dr. Pandharipande received a research grant from Hospira Inc, in collaboration with the NIH, and received grant funding from the NIH under award number R01HL111111. Dr. Ely has received honoraria from Pfizer and Lilly, and he has received grant funding from the NIH under award numbers R01AG027472, R01AG035117, R01HL111111, R01GM120484, and R01AG058639. Dr. Brummel received grant funding from the NIH, under award number K76AG054864. The remaining authors disclose that they do not have any other conflicts of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: Adult ICU survivors that experience delirium are at high risk for developing new functional disabilities and mental health disorders. We sought to determine if individual motoric subtypes of delirium are associated with worse disability, depression, and/or post-traumatic stress disorder in ICU survivors., Design: Secondary analysis of a prospective multicenter cohort study., Setting: Academic, community, and Veteran Affairs hospitals., Patients: Adult ICU survivors of respiratory failure and/or shock., Interventions: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation and Sedation Scale daily during hospitalization. We classified delirium as hypoactive (Richmond Agitation and Sedation Scale ≤ 0) or hyperactive (Richmond Agitation and Sedation Scale > 0). At 3- and 12-month postdischarge, we assessed for dependence in activities of daily living and instrumental activities of daily living, symptoms of depression, and symptoms of post-traumatic stress disorder. Adjusting for baseline and inhospital covariates, multivariable regression examined the association of exposure to delirium motoric subtype and long-term outcomes., Measurements and Main Results: In our cohort of 556 adults with a median age of 62 years, hypoactive delirium was more common than hyperactive (68.9% vs 16.8%). Dependence on the activities of daily living was present in 37% at 3 months and 31% at 12 months, whereas dependence on instrumental activities of daily living was present in 63% at 3 months and 56% at 12 months. At both time points, depression and post-traumatic stress disorder rates were constant at 36% and 5%, respectively. Each additional day of hypoactive delirium was associated with higher instrumental activities of daily living dependence at 3 months only (0.24 points [95% CI, 0.07-0.41; p = 0.006]). There were no associations between the motoric delirium subtype and activities of daily living dependence, depression, or post-traumatic stress disorder., Conclusions: Longer duration of hypoactive delirium, but not hyperactive, was associated with a minimal increase in early instrumental activities of daily living dependence scores in adult survivors of critical illness. Motoric delirium subtype was neither associated with early or late activities of daily living functional dependence or mental health outcomes, nor late instrumental activities of daily living functional dependence., Competing Interests: Dr. Boncyk received support from the National Institute of Health (NIH; 5T32GM108554); Dr. Patel received support from the NIH (AG058639, HL111111, and GM120484) and the Vanderbilt Faculty Research Scholars Program; Dr. Brummel received support from the NIH TR00046 and AG040549 and by the Vanderbilt Clinical and Translational Scholars Program; Dr. Ely received support from the NIH (AG058639, AG027472, AG035117, HL111111, and GM120484), the VA Clinical Science Research and Development Service, and the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center; Dr. Pandharipande received support from the NIH (AG027472, HL111111, and GM120484); Dr. Hughes received support from American Geriatrics Society Jahnigen Career Development Award and the NIH (HL111111, AG045085, and GM120484). We used Research Electronic Data Capture, a secure online database, supported in part by the NIH TR 000445. Dr. Rengel’s institution received funding from the NIH and the Department of Veterans Affairs. Drs. Jackson, Boncyk, Patel, Brummel, and Ely received support for article research from the NIH. Dr. Patel’s institution received funding from NIH R01 GM120484, NIH R01 AG058639, and VA Merit, RRD, and ORD, and he received funding from the NIH Center for Scientific Review, OLOL Trauma Symposium, Haemonetics, and from the Eastern Association for the Surgery of Trauma, Board of Directors. Dr. Brummel’s institution received funding from NIH, and he received funding from Merck. Dr. Ely received funding from Pfizer, Masimo, Kohler, and NIH/VA. Dr. Pandharipande received a research grant from Pfizer (previously from Hospira) in collaboration with NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown., Methods: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months., Results: Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups., Conclusions: Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.)., (Copyright © 2021 Massachusetts Medical Society.)

Rationale: The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear. Objectives: To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability. Methods: We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models). Measurements and Main Results: We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes. Conclusions: Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.

Background: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae., Methods: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression., Findings: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU., Interpretation: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19., Funding: None., Translations: For the French and Spanish translations of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Improved ability to predict impairments after critical illness could guide clinical decision-making, inform trial enrollment, and facilitate comprehensive patient recovery. A systematic review of the literature was conducted to investigate whether physical, cognitive, and mental health impairments could be predicted in adult survivors of critical illness., Data Sources: A systematic search of PubMed and the Cochrane Library (Prospective Register of Systematic Reviews ID: CRD42018117255) was undertaken on December 8, 2018, and the final searches updated on January 20, 2019., Study Selection: Four independent reviewers assessed titles and abstracts against study eligibility criteria. Studies were eligible if a prediction model was developed, validated, or updated for impairments after critical illness in adult patients. Discrepancies were resolved by consensus or an independent adjudicator., Data Extraction: Data on study characteristics, timing of outcome measurement, candidate predictors, and analytic strategies used were extracted. Risk of bias was assessed using the Prediction model Risk Of Bias Assessment Tool., Data Synthesis: Of 8,549 screened studies, three studies met inclusion. All three studies focused on the development of a prediction model to predict (1) a mental health composite outcome at 3 months post discharge, (2) return-to-pre-ICU functioning and residence at 6 months post discharge, and (3) physical function 2 months post discharge. Only one model had been externally validated. All studies had a high risk of bias, primarily due to the sample size, and statistical methods used to develop and select the predictors for the prediction published model., Conclusions: We only found three studies that developed a prediction model of any post-ICU impairment. There are several opportunities for improvement for future prediction model development, including the use of standardized outcomes and time horizons, and improved study design and statistical methodology.

Objectives: Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of frailty with disability and cognitive impairment in survivors of critical illness., Design: Longitudinal prospective cohort study., Setting: Medical and surgical ICUs at five U.S. centers., Patients: Adult patients treated for respiratory failure and/or shock., Measurements and Main Results: We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51-70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone., Conclusions: Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.

Objectives: Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition., Design: Secondary analysis of prospective multicenter cohort study., Setting: Academic, community, and Veteran Affairs hospitals., Patients: Five-hundred eighty-two survivors of respiratory failure or shock., Interventions: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates., Measurements and Results: Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (-5.13 [-8.75 to -1.51]; p = 0.03) but not 12 (-5.76 [-9.99 to -1.53]; p = 0.08) months and with worse executive functioning at 3 (-3.61 [-7.48 to 0.26]; p = 0.03) and 12 (-6.22 [-10.12 to -2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort., Conclusions: Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium.

Purpose: Delirium is prevalent but with unclear pathogenesis. Neuronal injury repair pathways may be protective. We hypothesized that higher concentrations of neuronal repair biomarkers would be associated with decreased delirium in critically ill patients., Materials and Methods: We performed a nested study of hospital survivors within a prospective cohort that enrolled patients within 72 h of respiratory failure or shock. We measured plasma concentrations of ubiquitin carboxyl-terminal-esterase-L1 (UCHL1) and brain-derived neurotrophic factor (BDNF) from blood collected at enrollment. Delirium was assessed twice daily using the CAM-ICU. Multivariable regression was used to examine the associations between biomarkers and delirium prevalence/duration, adjusting for covariates and interactions with age and IL-6 plasma concentration., Results: We included 427 patients with a median age of 59 years (IQR 48-69) and APACHE II score of 25 (IQR 19-30). Higher plasma concentration of UCHL1 on admission was independently associated with lower prevalence of delirium (p = .04) but not associated with duration of delirium (p = .06). BDNF plasma concentration was not associated with prevalence (p = .26) or duration of delirium (p = .36)., Conclusions: During critical illness, higher UCHL1 plasma concentration is associated with lower prevalence of delirium; BDNF plasma concentration is not associated with delirium. Clinical trial number: NCT00392795; https://clinicaltrials.gov/ct2/show/NCT00392795., Competing Interests: Declaration of Competing Interest The authors declare no competing interests in the past 36 months., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The clinical approach to the critically ill patient has changed dramatically over the last several decades from one of deep sedation to that of mobilizing patients on mechanical ventilation and limiting sedation. The ABCDEF bundle is a multidisciplinary, evidence-based approach to the holistic management of critically ill patients that aims to optimize patient recovery, minimize iatrogenesis, and engage and empower the patient and family during their hospitalization. To achieve this goal, the bundle includes assessments for pain, delirium, and readiness to stop sedation and to start spontaneous breathing trials. It also encourages early mobilization of the patient, avoidance of restraints, and engagement with the family in bedside rounds to improve communication. Performance of this bundle reduces mortality, ventilator days, intensive care readmissions, delirium, coma, restraint use, and discharge to facilities in a dose-dependent manner. The respiratory therapist, as a key member of the critical care team, is essential to the implementation, performance, and success of the ABCDEF bundle. This review aims to describe each component of the ABCDEF bundle, provide evidence for both the impact of individual interventions as well as the entire bundle, and detail the importance of this multidisciplinary approach to the care of the critically ill patient., (Copyright © 2019 by Daedalus Enterprises.)

Objective: To determine whether deficits in a key aspect of executive functioning, namely, initiation, were associated with current and future functional disabilities in intensive care unit survivors., Methods: A nested substudy within a 2-center prospective observational cohort. We used 3 tests of initiation at 3 and 12 months: the Ruff Total Unique Design, Controlled Oral Word Association, and Behavior Rating Inventory of Executive Function initiation. Disability in instrumental activities of daily living (IADL) was measured with the Functional Activities Questionnaire. We used a proportional odds logistic regression model to evaluate the association between initiation and disability. Covariates in the model included age, education, baseline Functional Activities Questionnaire, pre-existing cognitive impairment, comorbidities, admission severity of illness, episodes of hypoxia, and days of severe sepsis., Results: In 195 patients, after adjusting for covariates, only the Behavior Rating Inventory of Executive Function initiation was associated with disability at any time point. Comparing the 25th vs the 75th percentile scores (95% confidence interval) of the Behavior Rating Inventory of Executive Function initiation at 3 months, patients with worse initiation scores had 5.062 times the odds (95% confidence interval: 2.539, 10.092) of disability according to the Functional Activities Questionnaire at 3 months, with similar odds at 12 months (odds ratio: 3.476, 95% confidence interval: 1.943, 6.216). Worse Behavior Rating Inventory of Executive Function initiation scores at 3 months were associated with future disability at 12 months odds ratio (95% confidence interval) 5.079 (2.579, 10.000)., Conclusions: Executive function deficits acquired after a critical illness in the domain of initiation are common in intensive care unit survivors, and when they are identified via self-report tools, they are associated with current and future disability in instrumental activities of daily living., (Copyright © 2018 Academy of Consultation-Liaison Psychiatry. All rights reserved.)

Delirium is an acute and transient brain dysfunction that is characterized by disturbances in consciousness, affecting both its content (i.e., attention) and level (i.e., arousal). It affects as many as 50% of those admitted to an intensive care unit (ICU). Once believed to be an inconsequential outcome of critical illness, it is now recognized that delirium is harmful in both the short- and long-term. Despite occurring frequently in critically ill patients, delirium often goes unrecognized. Well-validated delirium screening tools, designed for use in the ICU, should be used to reliably detect delirium. The first step in delirium treatment is to identify and address potentially modifiable risk factors. Multiple trials have shown that benzodiazepines are a risk factor for delirium in a dose-dependent manner. Sedation with nonbenzodiazepine-based strategies are an effective means by which to reduce delirium. Nonpharmacologic strategies such as those which seek to reduce sensory impairment, sleep deprivation, and immobility are effective. Pharmacologic treatment with antipsychotics, though commonly used, is not supported by findings from placebo-controlled trials. Recent data support from multiple trials support the use of the "ABCDEF bundle" as a means by which to reduce delirium., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU)., Methods: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation., Results: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms., Conclusions: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

Outcomes after critical illness remain poorly understood. Conceptual models developed by other disciplines can serve as a framework by which to increase knowledge about outcomes after critical illness. This article reviews 3 models to understand the distinct but interrelated content of outcome domains, to review the components of functional status, and to describe how injuries and illnesses relate to disabilities and impairments afterward., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Objectives: To describe the frequency of co-occurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to evaluate predictors of being free of post-intensive care syndrome problems., Design: Prospective cohort study., Setting: Medical and surgical ICUs from five U.S. centers., Patients: Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings., Interventions: None., Measurements and Main Results: At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, co-occurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p < 0.001 at 3 and 12 mo). More severe frailty was associated with lower odds of being post-intensive care syndrome free (p = 0.005 at 3 mo and p = 0.048 at 12 mo)., Conclusions: In this multicenter cohort study, one or more post-intensive care syndrome problems were present in the majority of survivors, but co-occurring problems were present in only one out of four. Education was protective from post-intensive care syndrome problems and frailty predictive of the development of post-intensive care syndrome problems. Future studies are needed to understand better the heterogeneous subtypes of post-intensive care syndrome and to identify modifiable risk factors.

Objectives: Acute kidney injury frequently complicates critical illness and is associated with high morbidity and mortality. Frailty is common in critical illness survivors, but little is known about the impact of acute kidney injury. We examined the association of acute kidney injury and frailty within a year of hospital discharge in survivors of critical illness., Design: Secondary analysis of a prospective cohort study., Setting: Medical/surgical ICU of a U.S. tertiary care medical center., Patients: Three hundred seventeen participants with respiratory failure and/or shock., Interventions: None., Measurements and Main Results: Acute kidney injury was determined using Kidney Disease Improving Global Outcomes stages. Clinical frailty status was determined using the Clinical Frailty Scale at 3 and 12 months following discharge. Covariates included mean ICU Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation II score as well as baseline comorbidity (i.e., Charlson Comorbidity Index), kidney function, and Clinical Frailty Scale score. Of 317 patients, 243 (77%) had acute kidney injury and one in four patients with acute kidney injury was frail at baseline. In adjusted models, acute kidney injury stages 1, 2, and 3 were associated with higher frailty scores at 3 months (odds ratio, 1.92; 95% CI, 1.14-3.24; odds ratio, 2.40; 95% CI, 1.31-4.42; and odds ratio, 4.41; 95% CI, 2.20-8.82, respectively). At 12 months, a similar association of acute kidney injury stages 1, 2, and 3 and higher Clinical Frailty Scale score was noted (odds ratio, 1.87; 95% CI, 1.11-3.14; odds ratio, 1.81; 95% CI, 0.94-3.48; and odds ratio, 2.76; 95% CI, 1.34-5.66, respectively). In supplemental and sensitivity analyses, analogous patterns of association were observed., Conclusions: Acute kidney injury in survivors of critical illness predicted worse frailty status 3 and 12 months postdischarge. These findings have important implications on clinical decision making among acute kidney injury survivors and underscore the need to understand the drivers of frailty to improve patient-centered outcomes.

Purpose: Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood-brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge., Methods: We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants' global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates., Results: Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months., Conclusions: S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury.

Background: Delirium during critical illness results from numerous insults, which might be interconnected and yet individually contribute to long-term cognitive impairment. We sought to describe the prevalence and duration of clinical phenotypes of delirium (ie, phenotypes defined by clinical risk factors) and to understand associations between these clinical phenotypes and severity of subsequent long-term cognitive impairment., Methods: In this multicentre, prospective cohort study, we included adult (≥18 years) medical or surgical ICU patients with respiratory failure, shock, or both as part of two parallel studies: the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, and the Delirium and Dementia in Veterans Surviving ICU Care (MIND-ICU) study. We assessed patients at least once a day for delirium using the Confusion Assessment Method-ICU and identified a priori-defined, non-mutually exclusive phenotypes of delirium per the presence of hypoxia, sepsis, sedative exposure, or metabolic (eg, renal or hepatic) dysfunction. We considered delirium in the absence of hypoxia, sepsis, sedation, and metabolic dysfunction to be unclassified. 3 and 12 months after discharge, we assessed cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We used multiple linear regression to separately analyse associations between the duration of each phenotype of delirium and RBANS global cognition scores at 3-month and 12-month follow-up, adjusting for potential confounders., Findings: Between March 14, 2007, and May 27, 2010, 1048 participants were enrolled, eight of whom could not be analysed. Of 1040 participants, 708 survived to 3 months of follow-up and 628 to 12 months. Delirium was common, affecting 740 (71%) of 1040 participants at some point during the study and occurring on 4187 (31%) of all 13 434 participant-days. A single delirium phenotype was present on only 1355 (32%) of all 4187 participant-delirium days, whereas two or more phenotypes were present during 2832 (68%) delirium days. Sedative-associated delirium was most common (present during 2634 [63%] delirium days), and a longer duration of sedative-associated delirium predicted a worse RBANS global cognition score 12 months later, after adjusting for covariates (difference in score comparing 3 days vs 0 days: -4·03, 95% CI -7·80 to -0·26). Similarly, longer durations of hypoxic delirium (-3·76, 95% CI -7·16 to -0·37), septic delirium (-3·67, -7·13 to -0·22), and unclassified delirium (-4·70, -7·16 to -2·25) also predicted worse cognitive function at 12 months, whereas duration of metabolic delirium did not (1·14, -0·12 to 3·01)., Interpretation: Our findings suggest that clinicians should consider sedative-associated, hypoxic, and septic delirium, which often co-occur, as distinct indicators of acute brain injury and seek to identify all potential risk factors that may impact on long-term cognitive impairment, especially those that are iatrogenic and potentially modifiable such as sedation., Funding: National Institutes of Health and the Department of Veterans Affairs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The prognostic importance of subsyndromal delirium is unknown., Objective: To test whether duration of subsyndromal delirium is independently associated with institutionalization., Methods: The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used twice daily to assess for subsyndromal delirium in patients with respiratory failure or shock. Delirium was considered present if the assessment was positive. Subsyndromal delirium was considered present if the assessment was negative but the patient exhibited any CAM-ICU features. Multivariable regression was used to determine the association between duration of subsyndromal delirium and institutionalization, adjusting for age, education, baseline cognition and disability, comorbidities, severity of illness, delirium, coma, sepsis, and doses of sedatives and opiates., Results: Subsyndromal delirium, lasting a median of 3 days, developed in 702 of 821 patients (86%). After adjusting for covariates, duration of subsyndromal delirium was an independent predictor of increased odds of institutionalization ( P = .007). This association was greatest in patients with less delirium ( P for interaction = .01). Specifically, of patients who were never delirious, those with 5 days of subsyndromal delirium (upper interquartile range [IQR]) were 4.2 times more likely to be institutionalized than those with 1.5 days of subsyndromal delirium (lower IQR)., Conclusions: Subsyndromal delirium occurred in most critically ill patients, and its duration was an independent predictor of institutionalization. Routine monitoring of all delirium symptoms may enable detection of full and subsyndromal forms of delirium., (©2017 American Association of Critical-Care Nurses.)

Rationale: The prevalence of frailty (diminished physiologic reserve) and its effect on outcomes for those aged 18 years and older with critical illness is unclear., Objectives: We hypothesized greater frailty would be associated with subsequent mortality, disability, and cognitive impairment, regardless of age., Methods: 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., Measurements and Main Results: 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., Conclusions: 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).

Objective: The aim of this study was to determine whether surgery and anesthesia exposure is an independent risk factor for cognitive impairment after major noncardiac surgery associated with critical illness., Summary of Background Data: Postoperative cognitive impairment is a prevalent individual and public health problem. Data are inconclusive as to whether this impairment is attributable to surgery and anesthesia exposure versus patients' baseline factors and hospital course., Methods: In a multicenter prospective cohort study, we enrolled ICU patients with major noncardiac surgery during hospital admission and with nonsurgical medical illness. At 3 and 12 months, we assessed survivors' global cognitive function with the Repeatable Battery for the Assessment of Neuropsychological Status and executive function with the Trail Making Test, Part B. We performed multivariable linear regression to study the independent association of surgery/anesthesia exposure with cognitive outcomes, adjusting initially for baseline covariates and subsequently for in-hospital covariates., Results: We enrolled 1040 patients, 402 (39%) with surgery/anesthesia exposure. Median global cognition scores were similar in patients with surgery/anesthesia exposure compared with those without exposure at 3 months (79 vs 80) and 12 months (82 vs 82). Median executive function scores were also similar at 3 months (41 vs 40) and 12 months (43 vs 42). Surgery/anesthesia exposure was not associated with worse global cognition or executive function at 3 or 12 months in models incorporating baseline or in-hospital covariates (P > 0.2). Higher baseline education level was associated with better global cognition at 3 and 12 months (P < 0.001), and longer in-hospital delirium duration was associated with worse global cognition (P < 0.02) and executive function (P < 0.01) at 3 and 12 months., Conclusions: Cognitive impairment after major noncardiac surgery and critical illness is not associated with the surgery and anesthesia exposure but is predicted by baseline education level and in-hospital delirium.

Objectives: To determine how delirium subtyped by level of arousal at initial presentation affects 6-month mortality., Design: This was a preplanned secondary analysis of two prospective cohort studies., Setting: Academic tertiary care emergency department (ED)., Participants: 1,084 ED patients who were 65 years old or older., Measurements: At the time of enrollment, trained research personnel performed the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation Sedation Score to determine delirium and level of arousal, respectively. Patients were categorized as having no delirium, delirium with normal arousal, delirium with decreased arousal, or delirium with increased arousal. Death was ascertained by medical record review and the Social Security Death Index. Cox proportional hazard regression was used to analyze the association between delirium arousal subtypes and 6-month mortality., Results: Delirium with normal arousal was the only subtype that was significantly associated with increased 6-month mortality (hazard ratio [HR]: 3.1, 95% confidence interval [CI]: 1.3-7.4) compared with the no delirium group after adjusting for confounders. The HRs for delirium with decreased and increased arousal were 1.4 (95% CI: 0.9-2.1) and 1.3 (95% CI: 0.3-5.4), respectively., Conclusions: Delirious ED patients with normal arousal at initial presentation had a threefold increased hazard of death within 6 months compared with patients without delirium. There was a trend towards increased hazard of death in delirious ED patients with decreased arousal, but this relationship did not reach statistical significance. These data suggest that subtyping delirium by arousal may have prognostic value but requires confirmation with a larger study., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To characterize survivors' employment status after critical illness and to determine if duration of delirium during hospitalization and residual cognitive function are each independently associated with decreased employment., Design: Prospective cohort investigation with baseline and in-hospital clinical data and follow-up at 3 and 12 months., Setting: Medical and surgical ICUs at two tertiary-care hospitals., Patients: Previously employed patients from the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors study who survived a critical illness due to respiratory failure or shock were evaluated for global cognition and employment status at 3- and 12-month follow-up., Measurements and Main Results: We used multivariable logistic regression to evaluate independent associations between employment at both 3 and 12 months and global cognitive function at the same time point, and delirium during the hospital stay. At 3-month follow-up, 113 of the total survival cohort of 448 (25%) were identified as being employed at study enrollment. Of these, 94 survived to 12-month follow-up. At 3- and 12-month follow-up, 62% and 49% had a decrease in employment, 57% and 49% of whom, respectively, were newly unemployed. After adjustment for physical health status, depressive symptoms, marital status, level of education, and severity of illness, we did not find significant predictors of employment status at 3 months, but better cognition at 12 months was marginally associated with lower odds of employment reduction at 12 months (odds ratio, 0.49; p = 0.07)., Conclusions: Reduction in employment after critical illness was present in the majority of our ICU survivors, approximately half of which was new unemployment. Cognitive function at 12 months was a predictor of subsequent employment status. Further research is needed into the potential relationship between the impact of critical illness on cognitive function and employment status.