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

To determine the association between postoperative delirium (POD) and cognitive outcomes at least 1 month after surgery in elderly patients, and synthesize the dynamic risk trajectory of cognition impairment after POD. Meta-analysis searching PubMed, Cochrane and EMBASE from inception to November 1, 2020. The terms postoperative delirium, delirium after surgery, postsurgical delirium, postoperative cogniti*, postoperative cognitive dysfunction, postoperative cognition decline, cognitive decline, cognitive impair* and dement* were searched alone or in combination. Inclusion criteria were prospective cohort studies investigating the association between POD and cognitive outcomes in patients aged ≥60 years underwent surgery. The primary outcome was the association between POD and cognitive outcomes at 1 or more months after surgery. We considered cognitive outcomes measured up to 12 months after surgery as short-term and beyond 12 months as long-term. Two authors performed the study screening, data extraction and quality assessments. Effect sizes were calculated as Hedges g or Odds ratio (OR) based on random- and fixed-effects models. Meta-regression was conducted to analyze the role of potential contributors to heterogeneity. Eighteen studies were included. Our result showed a significant and medium association between POD and cognitive outcomes after at least 1 month postoperatively (g = 0.61 95% CI 0.43–0.79; I2 = 65.1%), indicating that patients with POD were associated with worse cognitive outcomes. The association of POD with short- and long-term cognitive impairment were also both significant (short-term: g = 0.46 95% CI 0.24–0.68; I2 = 53.1%; and long-term: g = 0.82 95% CI 0.57–1.06; I2 = 57.1%). A multivariate meta-regression suggested that age and measure of delirium were significant sources of heterogeneity. POD was also associated with the significant risk for dementia (OR = 6.08 95% CI 3.80–9.72; I2 = 0) as well as attention (OR = 1.74 95% CI 1.13–2.68; I2 = 0), executive (OR = 1.33 95% CI 1.00–1.80; I2 = 0) and memory impairment (OR = 1.59 95% CI 1.20–2.10; I2 = 43.0%). Additionally, our results showed that the risk trajectory for cognitive decline associated with POD within five years after surgery revealed exponential growth. This is the first meta-analysis quantifying the association between POD and cognitive outcomes. Our results showed that POD was significantly associated with worse cognitive outcomes, including short- and long-term cognitive outcomes following surgery. •POD was significantly associated with worse short- and long-term cognitive outcomes.•POD was associated with dementia as well as attention, execution and memory damage.•The relation between POD and cognitive impairment was time- and dose-dependent.

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.

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

Abstract Rationale The incidence and risk factors of post-traumatic stress disorder (PTSD) related to the intensive care unit (ICU) experience have not been reported in a mixed veteran and civilian cohort. Objectives To describe the incidence and risk factors for ICU-related PTSD in veterans and civilians. Methods This is a prospective, observational, multicenter cohort enrolling adult survivors of critical illness after respiratory failure and/or shock from three Veterans Affairs and one civilian hospital. After classifying those with/without preexisting PTSD (i.e., PTSD before hospitalization), we then assessed all subjects for ICU-related PTSD at 3 and 12 months post hospitalization. Measurements and Main Results Of 255 survivors, 181 and 160 subjects were assessed for ICU-related PTSD at 3- and 12-month follow-up, respectively. A high probability of ICU-related PTSD was found in up to 10% of patients at either follow-up time point, whether assessed by PTSD Checklist Event-Specific Version (score ≥ 50) or item mapping using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). In the multivariable regression, preexisting PTSD was independently associated with ICU-related PTSD at both 3 and 12 months (P < 0.001), as was preexisting depression (P < 0.03), but veteran status was not a consistent independent risk factor for ICU-related PTSD (3-month P = 0.01, 12-month P = 0.48). Conclusions This study found around 1 in 10 ICU survivors experienced ICU-related PTSD (i.e., PTSD anchored to their critical illness) in the year after hospitalization. Preexisting PTSD and depression were strongly associated with ICU-related PTSD.

Background Prior retrospective cross-sectional work has associated antimicrobials with a non-specific phrase: encephalopathy without seizures. The purpose of this study is to determine whether different classes of antimicrobials have differential associations with the daily risk of delirium after critical illness is adjusted for. Methods Our study was a nested cohort that enrolled non-neurological critically ill adults from a medical or surgical intensive care unit (ICU) with daily follow-up to 30 days. Our independent variable was exposure to previous-day antimicrobial class: beta-lactams (subclasses: penicillins, first- to third-generation cephalosporins, fourth-generation cephalosporins, and carbapenems), macrolides, fluoroquinolones, and other. We adjusted for baseline covariates (age, comorbidities, cognition scores, sepsis, and mechanical ventilation), previous-day covariates (delirium, doses of analgesics/sedatives, and antipsychotic use), and same-day covariates (illness severity). Our primary outcome of delirium was measured by using the Confusion Assessment Method for the ICU. A daily delirium logistic regression model was used with an ICU time-restricted sensitivity analysis including daily adjustment for sepsis and mechanical ventilation. Results Of 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2–6) among those affected and 318 (76%) were exposed to antimicrobials. When covariates and ICU type were adjusted for, only first- to third-generation cephalosporins were associated with delirium (logistic regression model odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.28–3.79, P = 0.004; sensitivity analysis OR = 2.13, 95% CI 1.10–4.10, P = 0.024). Conclusions First-, second-, and third-generation cephalosporins doubled the odds of delirium after baseline co-morbidities, ICU type, the course of critical care, and other competing antimicrobial and psychotropic medication risks were adjusted for. We did not find an association between delirium and cefepime, penicillins, carbapenems, fluoroquinolones, or macrolides.

Nearly half of patients who receive invasive mechanical ventilation for acute respiratory failure require over 4 days of ventilator support, each day of which is associated with increased morbidity, mortality and cost. Many of these patients develop expiratory muscle atrophy and weakness, which are linked to failed extubation and weaning. We seek to test the hypothesis that exhalation synchronised abdominal functional electrical stimulation reduces mechanical ventilation duration. This pivotal superiority trial will be performed in up to 30 intensive care units (ICUs) in the USA, France, the Netherlands and Australia. Adults (≥22 years old) who have been mechanically ventilated for 24-96 hours and are expected to remain ventilated for another 24+ hours are potentially eligible. We will recruit participants until 150 successful liberations from mechanical ventilation occur. To achieve this, we estimate that a maximum of 272 participants will be randomised in a 1:1 ratio to receive 30 min of active exhalation synchronised abdominal functional electrical stimulation (vs sham). The intervention will be applied using the VentFree Respiratory Muscle Stimulator two times per day, a minimum of 5 days per week, for a maximum of 28 days or until ICU discharge. The primary outcome is time from first intervention to successful liberation from mechanical ventilation. Secondary outcomes include cough peak flow (CPF) and maximum expiratory pressure (MEP) at 24 hours post-extubation, hospital and ICU length of stay, reintubations, complications, ICU readmissions, 90-day mortality and quality of life. The participant, clinical team and outcome assessor are blinded to group allocation. A positive outcome has the potential to improve patient-centred outcomes in ICUs. This study was approved by local ethics institutions in the USA, Australia, France and the Netherlands. We describe the methods herein using the Standard Protocol Items for Randomised Trials framework and discuss key design decisions. The results will be disseminated through peer-reviewed journal publications, conference presentations and clinicaltrials.gov updates. Individual country-level approvals are as follows:France:Ethics committee: Comité de Protection des Personnes Ile-de-France X.Reference numbers: CPP 27-2024; RCB 2024-A00559-38.Initial approval date: 14 May 2024.Australia:Ethics committee: South Eastern Sydney Local Health District Human Research Ethics Committee.Reference number: 2022/ETH02724.Initial approval date: 21 March 2023.Netherlands:Ethics committee: Medisch Ethische Toetsings Commissie Erasmus MC.Reference numbers: MEC-2023-0364; NL84195.000.23.Initial approval date: 30 April 2024.USA:Ethics committee: WCG IRB.IRB tracking number: 20214073.Initial approval date: 13 March 2023.All participating sites are currently approved and operating under protocol version 09 or later. NCT05759013. Registered 8 March 2023.

Background This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. Methods Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. Results The mean age-at-death was 66.2 years (range: 26–97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. Conclusions Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Background In longitudinal critical care studies, researchers may be interested in summarizing an exposure over time and evaluating its association with a long-term outcome. For example, the number of days a patient has delirium (i.e., brain dysfunction) during their critical care stay is associated with the presence and severity of long-term cognitive problems. In large pragmatic trials and multicenter observational studies, particularly when electronic medical record data is used, the information on daily exposure status may be available at some time points and not at others. Model-based multiple imputation is a well-established, widely adopted method to deal with missing data. But the uncertainty around multiple imputation for summary exposure variables is whether the imputation is to be performed at the summary level or at the daily assessment level. Methods We compare the following approaches to imputing and summarizing partially missing longitudinal data: 1) active imputation, where we impute the summary; 2) passive imputation, where we impute the daily missing data, and then compute the summary; 3) ad hoc methods where we assume all missing time points have the a) most or the b) least extreme value; and 4) complete case analysis where only participants with complete data are analyzed. These methods were applied under different missingness mechanisms, varying proportions of missingness, and association of missingness with an auxiliary variable using simulations that closely mirrors real-life critical care data to be relevant to real-world clinical practice. The performance of the approaches were compared using bias of the estimated coefficients, standard error of the estimate and coverage. We also apply these imputation strategies to two datasets in critical care. Results Simulations show that all methods performed comparably when the proportion of missingness was small, indicating that in such instances, the gain over using any imputation model is minimal. But as the proportion of missingness increases, the passive imputation approach provides efficient and less biased estimates under the missingness at random and missingness completely at random mechanism. Conclusions For longitudinal data where a summary exposure is of interest, we recommend practitioners adopting the passive imputation strategy.

Objective: The brain compensation mechanism in postoperative delirium (POD) has not been reported. We uncovered the mechanism by exploring the association between POD and glioma grades, and the relationship between preoperative brain structural and functional compensation with POD in frontal glioma patients. Methods: 335 adult glioma patients were included. The multivariable analysis was examined the association between tumor grade and POD. Then 20 patients with left frontal lobe glioma who had presurgical structural and functional magnetic resonance imaging (MRI) data and Montreal Cognitive Assessment (MoCA) in this cohort were analyzed. We measured gray matter volume (GMV) and functional connectivity (FC) in patients with (n=8) and without (n=12) POD and healthy controls (HCs) to detect the correlation between the structural and functional alteration and POD. Results: The incidence of POD was 37.3 %. Multivariable regression revealed that high-grade glioma had approximately six times the odds of POD. Neuroimaging data showed that compared with HC, the patients with left frontal lobe glioma showed significantly increased GMV of right dorsal lateral prefrontal cortex (DLPFC) in non-POD group and decreased GMV of right DLPFC in POD group, and POD group exhibited significantly decreased FC of right DLPFC, and the non-POD group showed the increasing tendency. Partial correlation analysis showed that GMV in contralesional DLPFC were positively correlated with preoperative neurocognition, and the GMV and FC in contralesional DLPFC were negatively correlated with POD. Conclusions: Our findinds suggested that insufficient compensation for injured brain region involving cognition might be more vulnerable to suffering from POD.