Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

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.

Systemic inflammation and delirium during critical illness.

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-1ß), 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-1ß, 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.

Exploring the Impact of Age, Frailty, and Multimorbidity on the Effect of ICU Interventions: A Systematic Review of Randomized Controlled Trials.

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.

Advancing specificity in delirium: The delirium subtyping initiative.

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.

In-hospital catatonia, delirium, and coma and mortality: Results from the delirium and catatonia prospective cohort investigation.

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.

Comparison of Fixed Dosing vs Train of Four Titration of Cisatracurium in COVID-19 ARDS Patients.

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.

Rehabilitation for People with Respiratory Disease and Frailty: An Official American Thoracic Society Workshop Report.

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.

Quantitative EEG signatures of delirium and coma in mechanically ventilated ICU patients.

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.

Association between cholinesterase activity and critical illness brain dysfunction.

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.

Physiologic responses to exercise in survivors of critical illness: an exploratory pilot study.

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 (VO2-work rate slope and VO2 recovery half-time). RESULTS: We recruited 14 participants. Low exercise capacity (i.e., VO2Peak < 80% predicted) was present in 11 out of 14 (79%) with a median VO2Peak of 12.6 ml/kg/min [9.6-15.1] and 6MWT distance of 294 m [240-433]. In addition to low VO2Peak, CPET findings in survivors included low oxygen uptake efficiency slope, low oxygen pulse, elevated chronotropic index, low VO2-work rate slope, and prolonged VO2 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 VO2-work rate slope and VO2 recovery half-time were strongly correlated with worse VO2Peak 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.

In-Hospital Depressed Level of Consciousness and Long-Term Functional Outcomes in ICU Survivors.

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.

Advanced Age Is Associated With Catatonia in Critical Illness: Results From the Delirium and Catatonia Prospective Cohort Investigation.

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.

Nutritional Risk at intensive care unit admission and outcomes in survivors of critical illness.

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.

Association of Delirium during Critical Illness With Mortality: Multicenter Prospective Cohort Study.

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.

Motoric Subtypes of Delirium and Long-Term Functional and Mental Health Outcomes in Adults After Critical Illness.

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.

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

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.).

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study.

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.