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IntroductionSurgery and its resulting hospitalisation are associated with subsequent cognitive and functional decline. Interventions to reduce this decline have exhibited limited success. Prehabilitation is the process of enhancing capacity and reserve before an acute stressor to improve tolerance of the acute physiologic insult. Older adults requiring major surgery are an ideal population for prehabilitation. Prehabilitation exercise studies have mostly focused on physical training to improve physical outcomes after specific surgery types, and data on cognitive outcomes and in broader surgical populations are needed. Computerised cognitive training (CCT) has been shown to enhance memory, processing speed, attention and multitasking. Combining CCT with a physical exercise may be most effective in reducing cognitive and functional decline in older patients undergoing major surgery, but has yet to be evaluated.Methods and analysisThe COgnitive and Physical Exercise to improve Outcomes after Surgery (COPE-iOS) study is a randomised, controlled, participant and assessor blinded clinical trial testing the hypothesis that a pragmatic programme combining CCT and physical exercise throughout the perioperative (ie, preoperative and postoperative) period will improve long-term cognitive and disability outcomes in older surgical patients at high risk for decline. The trial aims to randomise 250 patients who undergo major surgery for a treatment period of approximately 1 month prior to surgery and 3 months after surgery, with a follow-up period of 12 months after surgery. The primary outcome is global cognition at 3 months after surgery. Key secondary outcomes include global cognition at 12 months after surgery and disability in activities of daily living and depression at 3 and 12 months after surgery.Ethics and disseminationTrial protocol has been approved by Vanderbilt Human Research Protections Programme (#202496) and an independent Data Safety Monitoring Board. Results will be presented at scientific conferences and submitted for publication.Trial registration numberClinicalTrials.gov Registry NCT04889417.

Purpose While acute brain dysfunction (ABD, i.e., delirium and coma) is associated with significantly increased morbidity in critically ill patients, it presents with great heterogeneity that poses a challenge for management and prognostication. While machine learning may be promising for subgroup identification, this approach has not yet been applied to COVID-19 patients with ABD. The aim of our study was to identify distinct clusters among critically ill patients with COVID-19 based on ICU admission data and evaluate their association with clinical outcomes. Methods We retrospectively analyzed an international multicenter database (COVID-D study) of critically ill adult patients with COVID-19 during the first pandemic wave and ABD using clinical features on day 1 of admission as input variables. We applied unsupervised machine learning in a pilot attempt to discover clusters of ABD patients. Hierarchical clustering was performed with a bootstrap-based robustness assessment after dimensionality reduction. Clusters were analyzed for differences in neurological outcomes, mechanical ventilation, and survival. Results We analyzed 1,631 critically ill COVID-19 patients with ABD, identifying four reproducible clusters with distinct clinical and neurological profiles. Cluster 1 (\"mild respiratory failure,” n = 335) had the most favorable outcomes, with the shortest duration of delirium (4.13 days) and mechanical ventilation. Cluster 2 (\"moderate ARDS,\" n = 508) showed a comparable delirium incidence but the longest duration (5.18 days). Cluster 3 (\"early severe ARDS,\" n = 161) included patients who underwent prone positioning and mechanical ventilation early from the day of admission, with higher rates of coma (100%), including persistent coma (27.3%). Cluster 4 (\"late severe ARDS,\" n = 475) represented severely ill patients with the longest coma duration (11.2 days) and the lowest delirium-free and coma-free (DFCF) days (4.74), in relation to deep and prolonged sedation. Despite the wide range of ABD durations across four groups, no significantly different 28-day mortality (23.6–38.0, p > 0.78), ICU (15.8–19.2 days range, p = 0.154) and hospital (22.5–26.7 days range, p = 0.259) length of stay were observed among clusters. Conclusion This pilot analysis of ICU admission data from the first COVID-19 wave suggests the existence of clinically distinct clusters among patients with acute brain dysfunction. Differences were observed in the type and duration of delirium and coma, though these did not translate into differences in 28-day survival. This exploratory work may support targeted delirium prevention strategies, but prospective studies are required to determine its clinical utility in modern ICU settings. Graphical Abstract

Background The impact of specialist palliative care intervention in patients undergoing surgery for cancer has not been studied extensively. The SCOPE randomized controlled trial will investigate the effect of specialist palliative care intervention in cancer patients undergoing surgery for selected abdominal malignancies. The study protocol of the SCOPE Trial was published in December 2019. Methods and design The SCOPE Trial is a single-center, single-blind, prospective, randomized controlled trial that will investigate specialist palliative care intervention for cancer patients undergoing surgery for selected abdominal malignancies. The study plans to enroll 236 patients that will be randomized to specialist palliative care (intervention arm) and usual care (control arm) in a 1:1 ratio. Results The primary outcome of the study is the Functional Assessment of Cancer Therapy-General (FACT-G) Trial Outcome Index (TOI) at 90 days postoperatively. Secondary outcomes of the study include the total FACT-G score at 90 days postoperatively, days alive at home without an emergency room visit within 90 days of operation, and all-cause mortality at 1 year after operation. Time frames for all outcomes will start on the day of surgery. Conclusion This manuscript serves as the formal statistical analysis plan (version 1.0) for the SCOPE randomized controlled trial. The statistical analysis plan was completed on 6 April 2021. Trial registration ClinicalTrials.gov NCT03436290 . Registered on 16 February 2018

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

PurposeThe purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness.MethodsIn 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.ResultsAmong 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.ConclusionMarkers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

BackgroundWe sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months.MethodsThis was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively.FindingsTwo hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85).ConclusionPotentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms).