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Rationale: The epidemiology of hypoxemia in Sub-Saharan Africa is largely unknown., Objectives: Determine the prevalence, clinical care, and outcomes for hospitalized hypoxemic adults in Sub-Saharan Africa., Methods: We prospectively screened all adults admitted to five hospitals in Kenya, Malawi, and Rwanda over four months, and followed hypoxemic patients to discharge., Measurements and Main Results: Of the 24,724 adult patients admitted, 1,739 (7%) were hypoxemic on admission. Median imputed PaO 2 /FiO 2 was 168. Of all patients screened, 4,546 (18%) had complete oxygenation domains (SpO 2 , device, and quantity) documented in their charts on admission. Among hypoxemic patients, 44% of in-hospital days (6,890/15,553) had chart documentation of all three oxygenation domains. Of 1,508 unique hypoxemic patients, 770 (51%) had at least one day with subtherapeutic oxygen (SpO 2 <90%). Of patient-days with patients on oxygen therapy, 84% indicated supratherapeutic oxygen therapy (SpO 2 >94%). Of all hypoxemic adults, 35% died in-hospital. Sixteen percent of patients were mechanically ventilated during their stay, and in-hospital mortality in this subgroup was 49%., Conclusions: Hypoxemia is common and associated with high mortality in five referral hospitals in three countries in Sub-Saharan Africa. Monitoring and titration practices for oxygen therapy are inconsistent. Subtherapeutic and supratherapeutic oxygen therapy are common. Mortality is high among the few patients who receive mechanical ventilation. These findings suggest the urgent need to study interventions to improve survival for hypoxemic patients in Sub-Saharan Africa. Prioritized investigations include the development and implementation of oxygen monitoring and titration protocols, as well as studies of advanced oxygen therapies other than mechanical ventilation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

There are no approved treatments for post-COVID-19 condition (also known as long COVID), a debilitating disease state following SARS-CoV-2 infection that is estimated to affect tens of millions of people. A growing body of evidence shows that SARS-CoV-2 can persist for months or years following COVID-19 in a subset of individuals, with this reservoir potentially driving long-COVID symptoms or sequelae. There is, therefore, an urgent need for clinical trials targeting persistent SARS-CoV-2, and several trials of antivirals or monoclonal antibodies for long COVID are underway. However, because mechanisms of SARS-CoV-2 persistence are not yet fully understood, such studies require important considerations related to the mechanism of action of candidate therapeutics, participant selection, duration of treatment, standardisation of reservoir-associated biomarkers and measurables, optimal outcome assessments, and potential combination approaches. In addition, patient subgroups might respond to some interventions or combinations of interventions, making post-hoc analyses crucial. Here, we outline these and other key considerations, with the goal of informing the design, implementation, and interpretation of trials in this rapidly growing field. Our recommendations are informed by knowledge gained from trials targeting the HIV reservoir, hepatitis C, and other RNA viruses, as well as precision oncology, which share many of the same hurdles facing long-COVID trials., Competing Interests: Declaration of interests ADP reports a leadership role at PolyBio Research Foundation. SA reports research support from Gilead Sciences outside the submitted work and reimbursement for participation on Gilead's advisory board. MB reports consulting fees or payment honoraria for lectures from Bristol Myers Squibb, Mabtech, Pfizer, Gilead, and MSD outside of the submitted work, and participation on an advisory board for Mabtech. SGD reports research support from Aerium and Eli Lilly outside the submitted work and consulting for BioVie, Enanta Pharmaceuticals, and Pfizer. LNG reports research support from Pfizer outside the submitted work. AF serves as Chief Science and Medical Officer at Mead Johnson Nutrition. DEG reports research support from Gilead Sciences outside the submitted work and the leadership role of vice president at the National Academy of Sciences. AI reports being a member of the board of directors for Roche Holding and Genentech, being member of the Council for American Association of Immunologists, and being co-founder and stockholder of RIGImmune, Xanadu Bio, and PanV. In the past three years, HMK has received options for Element Science and Identifeye and payments from F-Prime for advisory roles. He is a cofounder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI. He is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer. VCM reports research support from Gilead Sciences, ViiV, CDC, NIH, Department of Veterans Affairs, and Merck outside the submitted work, participation on data safety monitoring or advisory boards for the IL-1b inhibitor study, Outsmart, CLEAR HIV, ECLIPSE, and VB201, and role of study section chair for NIH. YQ reports consulting for Moderna. DS reports honoraria for conferences on long COVID for Pfizer, Gilead, and Shionogi. EJW reports being an advisor for Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, and Synthekine; and being a founder of and holding stock in Coherus, Danger Bio, and Arsenal Biosciences. MBV reports a leadership role at PolyBio Research Foundation. JVW reports a speaker fee from Pfizer. MJP reports consulting for Gilead Sciences, BioVie, and AstraZeneca; and receipt of study drug from Aerium Therapeutics and Shionogi. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Millions of people around the world survive critical illness each year only to realize that they and their loved ones are grappling with a new "normal" after hospital discharge for which their medical team may not have adequately prepared them. Up to half of all ICU survivors suffer from new or worsening impairments in physical, cognitive, and psychological domains of health that are often not realized until they attempt to re-enter their previous lives. These devastating long-term sequelae of critical illness, collectively described as the postintensive care syndrome (PICS), can carry enormous consequences for an ICU survivor's ability to care for their family, return to work, and regain their previous quality of life for months to years after their inciting illness. Despite mounting research on PICS and survivorship, a knowledge gap exists whereby ICU team members may not always be aware of PICS and may not counsel their patients on the challenges awaiting them after discharge. Understanding how best to communicate these challenges to patients and families is crucial in preparing for survivorship beyond the ICU. In this review, we summarize PICS and possible recovery trajectories of ICU survivors. We then discuss communication strategies, emphasizing the role of empathy. Finally, we provide a suggested framework to handle these crucial conversations. We aim to equip clinicians with the knowledge and framework to care for a patient who has survived critical illness but now faces the possibility of struggles inadequately addressed by our health care system., Competing Interests: Financial/Nonfinancial Disclosures Supported by the National Heart, Lung and Blood Institute (T32HL087738; M. L. R). Supported by the National Institute on Aging (R01AG058969) and the U.S. Department of Veteran Affairs (I01RX002992; E. W. E.). None declared (M. F. M., J. C. J., C. M. S., M. E. W)., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Advances in critical care therapies for patients with cardiogenic shock (CS), including temporary mechanical circulatory support and multidisciplinary shock teams, have led to improved survival to hospital discharge, ranging from 60% to 70%. After their index hospitalization, however, survivors of CS may continue to face cardiac as well as extracardiac sequelae of these therapies and complications for years to come. Most studies in CS have focused primarily on survival, with limited data on long-term recovery measures among survivors. In other forms of critical illness, research indicates that many intensive care unit survivors experience impairments in multiple domains, such as cognitive function, physical ability, and mental health. These impairments, collectively referred to as Post-Intensive Care Syndrome, in turn impact survivors' quality of life and future prognosis. This review identifies unique aspects of CS-related survivorship, highlights lessons learned from other forms of critical illness, and outlines future research directions to determine specific strategies to enhance recovery and survivorship after CS., Competing Interests: Dr Hall is supported by the National Institutes of Health/National Heart Lung and Blood Institute (grant 5T32HL125247-8). Dr Agarwal is supported by grants R01-HL153311 and R01-NS127959 from the National Institutes of Health. Dr Cullum reports serving as the Scientific Director of the Texas Alzheimer’s Research and Care Consortium and receiving royalties from the Texas Functional Living Scale, published by Pearson, Inc. Dr Ely reports receiving research funding from the National Institutes of Health and the VA. The other authors report no relevant disclosures.

Outpatient care following nonhospitalized traumatic brain injury (TBI) is variable, and often sparse. The National Academies of Sciences, Engineering, and Medicine's 2022 report on Traumatic Brain Injury: A Roadmap for Accelerating Progress highlighted the need to improve the consistency and quality of TBI care in the community. In response, the present study aimed to identify existing evidence-based guidance and specific clinical actions over the days to months following nonhospitalized TBI that should be prioritized for implementation in primary care. In systematic literature searches, 17 clinical practice guidelines met our eligibility criteria and an additional expert consensus statement was considered highly relevant. We extracted 73 topics covered by one or more existing clinical practice guidelines. After removing redundant and out-of-scope topics, those deemed essential (not requiring prioritization), 42 topics were subjected to a prioritization exercise. Experts from the author group ( n = 14), people with lived experience ( n = 112), and clinicians in the community ( n = 99) selected and ranked topics they considered most important. There were areas of agreement (e.g., early education was ranked highly by all groups) and discordance (e.g., people with lived experience perceived diagnostic tests/investigations as more important than the other groups). We synthesized the prioritization survey results into a top-10 list of the highest priority clinical actions. This list will inform implementation efforts aimed at improving post-acute care for nonhospitalized TBI.

Background: Implementation of the "B" element-both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)-of the ABCDEF bundle improves the outcomes for mechanically ventilated patients. In 2021, the Pragmatic Investigation of optimal Oxygen Targets (PILOT) trial investigating optimal oxygenation targets in patients on mechanical ventilation was completed., Objectives: To compare SAT and SBT conduct between a randomized controlled trial and current clinical care., Methods: The 2008 Awakening and Breathing Controlled (ABC) Trial (2003-2006) randomized mechanically ventilated patients to paired SATs and SBTs versus sedation per usual care plus SBTs. The PILOT trial (2018-2021) enrolled patients years later where SAT + SBT conduct was observed. We compared SAT and SBT conduct in ABC's interventional group (SAT + SBT; n = 167, 1140 patient days) to that in PILOT (n = 2083, 8355 patient days)., Results: Spontaneous awakening trial safety screens were done in all 1140 ABC patient-days on sedation and/or analgesia and in 3889 of 4228 (92%) in PILOT. Spontaneous awakening trial safety screens were passed in 939 of 1140 (82%) instances in ABC versus only 1897 of 3889 (49%) in PILOT. Interestingly, SAT was performed in ≥95% of passed SAT safety screens in both trials and was passed in 837 of 895 (94%) in ABC versus 1145 of 1867 (61%) in PILOT. SBT safety screens were performed in all 983 ABC instances and 8031 of 8370 (96%) in PILOT. SBT safety screens were passed in 647 of 983 (66%) in ABC versus 4475 of 8031 (56%) in PILOT. Spontaneous breathing trial was performed in ≥93% of passed SBT safety screens in both trials and was passed in 319 of 603 (53%) in ABC versus 3337 of 4454 (75%) in PILOT., Conclusion: This study compared SAT/SBT conduction in an ideal setting to real-world practice, 13 years later. Performance of SAT/SBT safety screens, SATs, and SBTs between a definitive clinical trial (ABC) as compared to current clinical care (PILOT) remained high., 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.

Millions of Americans endure post-COVID conditions (PCC), yet research often lacks pre-illness measurements, relying primarily on follow-up assessments for analysis. The study aims to examine the prevalence of PCC, including cognitive impairment, functional limitation, and depressive symptoms, along with relevant risk factors, while controlling for individuals' pre-illness status measured in 2018. A cross-sectional retrospective study utilized the 2018 and 2020 Health and Retirement Study surveys. Sample included individuals with COVID-19 (n = 409; average age 64) and individuals without COVID-19 (n = 8689; average age 59). COVID-19 positive: Individuals with positive tests, physician diagnoses, emergency room visits, or hospitalizations for COVID-19 between 2019-2020. Cognition was assessed using immediate and delayed word-recall tests, serial seven subtractions, and backward counting. Functional status was measured using limitations in activities of daily living (ADLs) and instrumental ADLs. Depressive symptoms were measured using the modified Center for Epidemiology Studies Depression scale. Participants' perception of experiencing PCC was collected. Logistic regression and propensity score matching were employed for these analyses. Among 409 COVID-19-positive respondents (14% hospitalized), 24% exhibited new impairments after COVID-19 infection. Noteworthy increases in functional limitation (OR [95% CI]: 2.18 [0.95, 0.97], p < 0.001) and a marginal rise in cognitive impairment (1.79 [0.99, 3.32], p = 0.053) following COVID-19 infection were observed in comparison to their pre-COVID-19 baseline. Compared to 8689 non-COVID-19 cases, the 409 COVID-19 positives showed increased functional decline (1.78 [1.26, 2.51], p = 0.001) and depressive symptoms (1.41 [1.04, 1.91], p = 0.03). Factors associated with PCC included pre-existing impairments, lower education, female gender, prior hospitalization, higher comorbidity, lower wealth, and mild COVID-19. A notable number of respondents, especially older individuals with fewer pre-existing health conditions, experienced PCC without awareness. Compared to an individual's pre-illness baseline and uninfected individuals, being positive for COVID-19 raised the risk of functional limitation, depressive symptoms, and cognitive impairment. Additionally, addressing PCC through both subjective and objective approaches is essential to alleviate individual and societal burdens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Su et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Disorientation is an early indicator of developing postoperative delirium (POD), which is associated with increased mortality and cognitive decline. The well-established "Confusion-Assessment-Method-for-Intensive-Care-Unit" (CAM-ICU) for diagnosing POD in intubated patients cannot make use of the feature 'disorientation', as this requires verbal communication. Other tools such as the 4AT test for disorientation but are not established in ICU settings. We therefore combined test-variables of the CAM-ICU (level of consciousness, fluctuating mental status and inattention) with verbal testing for disorientation to develop and enhance diagnostic accuracy of the "Confusion Assessment Method for Intermediate Care Unit" (CAM-IMC). In the present study we describe the development and the evaluation of the diagnostic accuracy of the CAM-IMC., Methods: We conducted a prospective cohort-study to develop and evaluate the diagnostic accuracy of the CAM-IMC and disorientation for diagnosing POD in non-intubated patients undergoing elective cardiac surgery. All patients were eligible during data collection period. Exclusion criteria were preexisting brain-organic disease, age < 50 years, preoperative intubation, and insufficient language skills. Patients were assessed for POD using the CAM-IMC as the index-test by two independent examiners over three postoperative days. Reference-testing was conducted by experienced reference-raters. The primary outcome was the diagnostic test-performance., Results: Among 178 eligible patients, 624 paired observations were completed with 155 patients. Of these, 9% experienced POD. Sensitivity and specificity were 0.96 (CI-95%: 0.87-1.00) and 0.94 (CI-95%: 0.92-0.96), respectively. Area-Under-the-Receiver-Operating-Characteristic-Curve (AUROC; equivalent to c-statistic) for CAM-IMC with a cut-off at three points was 0.95 (CI-95%: 0.93-0.98). The interrater reliability was 0.80 (CI-95%: 0.69-0.91)., Conclusion: The CAM-IMC demonstrates excellent test performance for diagnosing POD in non-intubated patients by combining features of the CAM-ICU with 'disorientation'. Given an aging community with an increasing delirium risk, the CAM-IMC provides a highly structured assessment tool for POD. It enables early and accurate detection of delirium, which is critical for timely intervention and improved patient outcomes. The CAM-IMC appears to be a useful tool to be implemented in units for not-intubated patients and seems to be the perfect match where the CAM-ICU is already in use for monitoring POD., Trial Registration: DRKS00026980 (German registry of clinical studies)., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Medical Faculty of the Carl von Ossietzky University Oldenburg, Germany (No. 2020-020). It is registered in the German registry of clinical studies (DRKS00026980). All patients provided written informed consent. The study adheres to the principles of the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Advances in our approach to treating pain and sedation when caring for patients in the intensive care unit (ICU) have been propelled by decades of robust trial data, knowledge gained from patient experiences, and our evolving understanding of how pain and sedation strategies affect patient survival and long term outcomes. These data contribute to current practice guidelines prioritizing analgesia-first sedation strategies (analgosedation) that target light sedation when possible, use of short acting sedatives, and avoidance of benzodiazepines. Together, these strategies allow the patient to be more awake and able to participate in early mobilization and family interactions. The covid-19 pandemic introduced unique challenges in the ICU that affected delivery of best practices and patient outcomes. Compliance with best practices has not returned to pre-covid levels. After emerging from the pandemic and refocusing our attention on optimal pain and sedation management in the ICU, it is imperative to revisit the data that contributed to our current recommendations, review the importance of best practices on patient outcomes, and consider new strategies when advancing patient care., Competing Interests: Contributors: CB, EWE, and MR conceived the paper and wrote the first draft. All other authors revised the manuscript and provided critical feedback. CB and EWE act as guarantors. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Competing interests: CB and CGH received consulting fees from Sedana Medical as members of their US Trials Steering Committee. All other authors have no conflicts of interest to report., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: Neurocritically ill patients are at high risk for developing delirium, which can worsen the long-term outcomes of this vulnerable population. However, existing delirium assessment tools do not account for neurologic deficits that often interfere with conventional testing and are therefore unreliable in neurocritically ill patients. We aimed to determine the accuracy and predictive validity of the Fluctuating Mental Status Evaluation (FMSE), a novel delirium screening tool developed specifically for neurocritically ill patients., Design: Prospective validation study., Setting: Neurocritical care unit at an academic medical center., Patients: One hundred thirty-nine neurocritically ill stroke patients (mean age, 63.9 [ sd , 15.9], median National Institutes of Health Stroke Scale score 11 [interquartile range, 2-17])., Interventions: None., Measurements and Main Results: Expert raters performed daily Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based delirium assessments, while paired FMSE assessments were performed by trained clinicians. We analyzed 717 total noncomatose days of paired assessments, of which 52% ( n = 373) were rated by experts as days with delirium; 53% of subjects were delirious during one or more days. Compared with expert ratings, the overall accuracy of the FMSE was high (area under the curve [AUC], 0.85; 95% CI, 0.82-0.87). FMSE scores greater than or equal to 1 had 86% sensitivity and 74% specificity on a per-assessment basis, while scores greater than or equal to 2 had 70% sensitivity and 88% specificity. Accuracy remained high in patients with aphasia (FMSE ≥ 1: 82% sensitivity, 64% specificity; FMSE ≥ 2: 64% sensitivity, 84% specificity) and those with decreased arousal (FMSE ≥ 1: 87% sensitivity, 77% specificity; FMSE ≥ 2: 71% sensitivity, 90% specificity). Positive FMSE assessments also had excellent accuracy when predicting functional outcomes at discharge (AUC, 0.86 [95% CI, 0.79-0.93]) and 3 months (AUC, 0.85 [95% CI, 0.78-0.92])., Conclusions: In this validation study, we found that the FMSE was an accurate delirium screening tool in neurocritically ill stroke patients. FMSE scores greater than or equal to 1 indicate "possible" delirium and should be used when prioritizing sensitivity, whereas scores greater than or equal to 2 indicate "probable" delirium and should be used when prioritizing specificity., Competing Interests: Dr. Reznik’s institution received funding from the National Institute on Aging (NIA) and the Rhode Island Foundation; he is supported by the Network for Investigation of Delirium: Unifying Scientists (NIDUS) Junior Investigator Award (NIA R24AG054259 subaward). Drs. Reznik and Snitz received support for article research from the National Institutes of Health (NIH). Dr. Margolis’ institution received funding from the NIDUS; he received support for article research from NIDUS. Dr. Girard’s institution received funding from the NIH, the Department of Defense, Ceribell, and Lungpacer. 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.)

Rationale/objectives: Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU., Methods: A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified., Results: Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging., Conclusions: This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation., Competing Interests: Competing interests: MPK is a member of Serca LLC (no conflict with this review)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Surviving sepsis can lead to chronic physical, psychological and cognitive impairments, which affect millions of patients worldwide, including survivors after COVID-19 viral sepsis. We aimed to characterize the magnitude and trajectory of functional dependence and new impairments post-sepsis., Methods: We conducted a prospective cohort study including sepsis survivors who had been discharged from five German intensive care units (ICUs), until 36 months post-discharge. Primary outcome was functional dependence, defined as ≥1 impaired activity of daily living (ADL; 10-item ADL score <100), self-reported nursing care dependence or nursing care level. Secondary outcome was post-sepsis morbidity in the physical, psychological or cognitive domain. We used a multistate, competing risk model to address competing events in the course of dependence, and conducted multiple linear regression analyses to identify predictors associated with the ADL score., Findings: Of 3210 sepsis patients screened, 1968 survived the ICU treatment (61.3%). A total of 753 were included in the follow-up assessments of the Mid-German Sepsis cohort. Patients had a median age of 65 (Q1-Q3 56-74) years, 64.8% (488/753) were male and 76.1% (573/753) had a septic shock. Considering competing risk modelling, the probability of still being functional dependent was about 25%, while about 30% regained functional independence and 45% died within the three years post-sepsis. Patients reported a high burden of new and often overlapping impairments until three years post-sepsis. In the subgroup of three-year survivors (n = 330), new physical impairments affected 91.2% (n = 301) while new cognitive and psychological impairments were reported by 57.9% (n = 191) and 40.9% (n = 135), respectively. Patients with pre-existing functional limitations and higher age were at risk for low ADL scores three years after sepsis., Interpretation: Sepsis survivorship was associated with a broad range of new impairments and led to functional dependence in around one quarter of patients. Targeted measures are needed to mitigate the burden of this Post-Sepsis-Syndrome and increase the proportion of patients that achieve functional improvements., Funding: This work was supported by the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) at the Jena University Hospital funded by the German Ministry of Education and Research and by the Rudolf Presl GmbH & Co, Kreischa, Germany., Competing Interests: Over the past 5 years, Sven Bercker was investigator in studies sponsored by BioMeriéux, Boehringer Ingelheim, AM-Pharma B.V., Roche, Takeda, Dompé, and he is member of a DSMB for a study sponsored by hemotune AG. He has not received any personal fees for lectures or as a consultant or any reimbursement of travel expenses outside the sponsored studies. Konrad Reinhart holds shares from InflaRx NV, which is based in Jena, Germany and listed at NASDQ. This company recently received emergency use authorization by the FDA for an antibody against C5a—Gohibic (vilobelimab)—to treat critically ill COVID-19 patients, which fulfill the criteria for viral sepsis. E. Wesley Ely received NIH/VA Grant support. Over the last 36 months, the institution of Heinrich Groesdonk has received fees for his lectures, for his consultant activities, for his work in an advisory board or reimbursement for personal travel expenses by Edwards Lifescience, Amomed, and he personally holds shares from Fresenius SE. All other authors declare no conflict of interest., (© 2024 The Author(s).)

Background: Adoption of early mobility interventions into intensive care unit (ICU) practice has been slow and varied., Objectives: To examine factors associated with early mobility performance in critically ill adults and evaluate factors' effects on predicting next-day early mobility performance., Methods: A secondary analysis of 66 ICUs' data from patients admitted for at least 24 hours. Mixed-effects logistic regression modeling was done, with area under the receiver operating characteristic curve (AUC) calculated., Results: In 12 489 patients, factors independently associated with higher odds of next-day mobility included significant pain (adjusted odds ratio [AOR], 1.16; 95% CI, 1.09-1.23), documented sedation target (AOR, 1.09; 95% CI, 1.01-1.18), performance of spontaneous awakening trials (AOR, 1.77; 95% CI, 1.59-1.96), spontaneous breathing trials (AOR, 2.35; 95% CI, 2.14-2.58), mobility safety screening (AOR, 2.26; 95% CI, 2.04-2.49), and prior-day physical/occupational therapy (AOR, 1.44; 95% CI, 1.30-1.59). Factors independently associated with lower odds of next-day mobility included deep sedation (AOR, 0.44; 95% CI, 0.39-0.49), delirium (AOR, 0.63; 95% CI, 0.59-0.69), benzodiazepine administration (AOR, 0.85; 95% CI, 0.79-0.92), physical restraints (AOR, 0.74; 95% CI, 0.68-0.80), and mechanical ventilation (AOR, 0.73; 95% CI, 0.68-0.78). Black and Hispanic patients had lower odds of next-day mobility than other patients. Models incorporating patient, practice, and between-unit variations displayed high discriminant accuracy (AUC, 0.853) in predicting next-day early mobility performance., Conclusions: Collectively, several modifiable and nonmodifiable factors provide excellent prediction of next-day early mobility performance., (©2024 American Association of Critical-Care Nurses.)

Long-Covid (LC), Post-Sepsis-Syndrome (PSS) and Post-Intensive-Care-Syndrome (PICS) show remarkable overlaps in their clinical presentation. Nevertheless, it is unclear if they are distinct syndromes, which may co-occur in the same patient, or if they are three different labels to describe similar symptoms, assigned on the basis on patient history and professional perspective of the treating physician. Therefore, we reviewed the current literature on the relation between LC, PSS and PICS. To date, the three syndromes cannot reliably be distinguished due similarities in clinical presentation as they share the cognitive, psychological and physical impairments with only different probabilities of occurrence and a heterogeneity in individual expression. The diagnosis is furthermore hindered by a lack of specific diagnostic tools. It can be concluded that survivors after COVID-19 sepsis likely have more frequent and more severe consequences than patients with milder COVID-19 courses, and that are some COVID-19-specific sequelae, e.g. an increased risk for venous thromboembolism in the 30 days after the acute disease, which occur less often after sepsis of other causes. Patients may profit from leveraging synergies from PICS, PSS and LC treatment as well as from experiences gained from infection-associated chronic conditions in general. Disentangling molecular pathomechanisms may enable future targeted therapies that go beyond symptomatic treatment., (© 2024. The Author(s).)

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.)

Competing Interests: Dr. Ely received funding from the National Institute of Aging (R01 AG058639). Dr. Rolfsen has disclosed that he does not have any potential conflicts of interest.

Objectives: Understanding the long-term effects of severe COVID-19 illness on survivors is essential for effective pandemic recovery planning. Therefore, we investigated impairments among hospitalized adults discharged to long-term acute care hospitals (LTACHs) for prolonged severe COVID-19 illness who survived 1 year., Design: The Recovery After Transfer to an LTACH for COVID-19 (RAFT COVID) study was a national, multicenter, prospective longitudinal cohort study., Setting and Patients: We included hospitalized English-speaking adults transferred to one of nine LTACHs in the United States between March 2020 and February 2021 and completed a survey., Interventions: None., Measurements and Main Results: Validated instruments for impairments and free response questions about recovering. Among 282 potentially eligible participants who provided permission to be contacted, 156 (55.3%) participated (median age, 65; 38.5% female; 61.3% in good prior health; median length of stay of 57 d; 77% mechanically ventilated for a median of 26 d; 42% had a tracheostomy). Approximately two-thirds (64%) had a persistent impairment, including physical (57%), respiratory (49%; 19% on supplemental oxygen), psychiatric (24%), and cognitive impairments (15%). Nearly half (47%) had two or more impairment types. Participants also experienced persistent debility from hospital-acquired complications, including mononeuropathies and pressure ulcers. Participants described protracted recovery, attributing improvements to exercise/rehabilitation, support, and time. While considered life-altering with 78.7% not returning to their usual health, participants expressed gratitude for recovering; 99% returned home and 60% of previously employed individuals returned to work., Conclusions: Nearly two-thirds of survivors of among the most prolonged severe COVID-19 illness had persistent impairments at 1 year that resembled post-intensive care syndrome after critical illness plus debility from hospital-acquired complications., Competing Interests: Dr. Makam’s institution received funding from the University of California, San Francisco Research Evaluation and Allocation Committee Carson and Hampton Research Funds and the National Association of Long Term Hospitals (NALTH). Drs. Makam’s and Covinsky’s institutions received funding from the National Institute on Aging. Drs. Makam, Ely, Jackson, and Convinsky received support for article research from the National Institutes of Health. Dr. Prettyman disclosed that he is President of the NALTH. Dr. Espejo’s institution received funding from the Donaghue Foundation. Dr. Votto received funding from the NALTH; he disclosed that he is the Chief Medical Officer of NALTH. 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.)

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( β ^  = 0.671, p = 0.010). There were no significant differences in mortality ( β ^  = - 0.204, p = 0.561), ventilator duration ( β ^  = 0.016, p = 0.956), and ICU or hospital length of stay ( β ^  = - 0.134, p = 0.603; β ^  = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness., (© 2024. The Author(s).)

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.)

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown. Objectives: To compare the effects of lower (90% [range, 88-92%]), intermediate (94% [range, 92-96%]), and higher (98% [range, 96-100%]) oxygen-saturation targets on long-term outcomes. Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction. Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91-96%), 95% (93-97%), and 97% (95-99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92-2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62-1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83-1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life. Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.

During intensive care unit admission, relatives of critically ill patients can experience emotional distress. The authors hypothesized that families of patients who are diagnosed with intensive care unit (ICU) delirium experience more profound depression and anxiety disorders related to stress than do families of patients without delirium. We performed a prospective observational single-center study including families of adult patients (age above 18 years) hospitalized in a 17-bed ICU of a university hospital for at least 48 h who completed research questionnaires at day 2 after admission and day 30 after initial evaluation using dedicated questionnaires (HADS, CECS, IES, PTSD-C). A total of 98 family members of patients hospitalized in the ICU were included in the final analysis (50 family members whose relatives were CAM-ICU positive (DEL+), and 48 family members of patients without delirium (DEL-)). No statistically significant differences in demographics and psychosocial data were found between the groups. In the follow-up 30 days after the first conversation with a family member, the mean PTSD score for the relatives of patients with delirium was 11.02 (Me = 13.0; SD = 5.74), and the mean score for nondelirious patients' family members was 6.42 (Me = 5.5; SD = 5.50; p < 0.001). A statistically significant increase in IES scores for family members of patients with delirium was observed for total PTSD (p = 0.001), IES-intrusion (p < 0.001), and IES-hyperarousal (p = 0.002). The prevalence of anxiety symptoms, depression, and posttraumatic stress disorder (PTSD) was higher in families of patients diagnosed with ICU delirium within 48 h of admission to the ICU. No factors increasing the depth of these disorders in family members of patients with ICU delirium were identified. Taking appropriate actions and thus providing families with appropriate support will contribute to the understanding of unfavorable emotional states, including anxiety, stress, depression, anger, agitation, or avoidance., (© 2024. The Author(s).)

Acute Respiratory Distress Syndrome (ARDS) is an important global health issue with high in-hospital mortality. Importantly, the impact of ARDS extends beyond the acute phase, with increased mortality and disability for months to years after hospitalization. These findings underscore the importance of extended follow-up to assess and address the Post-Intensive Care Syndrome (PICS), characterized by persistent impairments in physical, cognitive, and/or mental health status that impair quality of life over the long-term. Persistent muscle weakness is a common physical problem for ARDS survivors, affecting mobility and activities of daily living. Critical illness and related interventions, including prolonged bed rest and overuse of sedatives and neuromuscular blocking agents during mechanical ventilation, are important risk factors for ICU-acquired weakness. Deep sedation also increases the risk of delirium in the ICU, and long-term cognitive impairment. Corticosteroids also may be used during management of ARDS, particularly in the setting of COVID-19. Corticosteroids can be associated with myopathy and muscle weakness, as well as prolonged delirium that increases the risk of long-term cognitive impairment. The optimal duration and dosage of corticosteroids remain uncertain, and there's limited long-term data on their effects on muscle weakness and cognition in ARDS survivors. In addition to physical and cognitive issues, mental health challenges, such as depression, anxiety, and post-traumatic stress disorder, are common in ARDS survivors. Strategies to address these complications emphasize the need for consistent implementation of the evidence-based ABCDEF bundle, which includes daily management of analgesia in concert with early cessation of sedatives, avoidance of benzodiazepines, daily delirium monitoring and management, early mobilization, and incorporation of family at the bedside. In conclusion, ARDS is a complex global health challenge with consequences extending beyond the acute phase. Understanding the links between critical care management and long-term consequences is vital for developing effective therapeutic strategies and improving the quality of life for ARDS survivors., (© 2024. The Author(s).)

Background: A lack of high-quality provider education hinders the delivery of standard-of-care delirium detection and prevention practices in the intensive care unit (ICU). To fill this gap, we developed and validated an e-learning ICU Delirium Playbook consisting of eight videos and a 44-question knowledge assessment quiz. Given the increasing Spanish-speaking population worldwide, we translated and cross-culturally adapted the playbook from English into Spanish., Objective: To translate and culturally adapt the ICU Delirium Playbook into Spanish, the second most common native language worldwide., Methods: The translation and cross-cultural adaptation process included double forward and back translations and harmonization by a 14-person interdisciplinary team of ICU nurses and physicians, delirium experts, methodologists, medical interpreters, and bilingual professionals representing many Spanish-speaking global regions. After a preeducation quiz, a nurse focus group completed the playbook videos and posteducation quiz, followed by a semistructured interview., Results: The ICU Delirium Playbook: Spanish Version maintained conceptual equivalence to the English version. Focus group participants posted mean (standard deviation) pre- and post-playbook scores of 63% (10%) and 78% (12%), with a 15% (11%) pre-post improvement ( P  = 0.01). Participants reported improved perceived competency in performing the Confusion Assessment Method for the ICU and provided positive feedback regarding the playbook., Conclusion: After translation and cultural adaptation, the ICU Delirium Playbook: Spanish Version yielded significant knowledge assessment improvements and positive feedback. The Spanish playbook is now available for public dissemination., (Copyright © 2024 by the American Thoracic Society.)

Background: To understand delirium heterogeneity, prior work relied on psychomotor symptoms or risk factors to identify subtypes. Data-driven approaches have used machine learning to identify biologically plausible, treatment-responsive subtypes of other acute illnesses but have not been used to examine delirium., Methods: We conducted a secondary analysis of a large, multicenter prospective cohort study involving adults in medical or surgical ICUs with respiratory failure or shock who experienced delirium per the Confusion Assessment Method for the ICU. We used data collected before delirium diagnosis in an unsupervised latent class model to identify delirium subtypes and then compared demographics, clinical characteristics, and outcomes between subtypes in the final model., Findings: The 731 patients who developed delirium during critical illness had a median age of 63 [IQR, 54-72] years, a median Sequential Organ Failure Assessment score of 8.0 [6.0-11.0] and 613 [83.4%] were mechanically ventilated at delirium identification. A four-class model best fit the data with 50% of patients in subtype (ST) 1, 18% in subtype 2, 17% in subtype 3, and 14% in subtype 4. Subtype 2-which had more shock and kidney impairment-had the highest mortality (33% [ST2] vs. 17% [ST1], 25% [ST3], and 17% [ST4], p = 0.003). Subtype 4-which received more benzodiazepines and opioids-had the longest duration of delirium (6 days [ST4] vs. 3 [ST1], 4 [ST2], and 3 days [ST3], p < 0.001) and coma (4 days [ST4] vs. 2 [ST1], 1 [ST2], and 2 days [ST3], p < 0.001). Each of the four data-derived delirium subtypes was observed within previously identified psychomotor and risk factor-based delirium subtypes. Clinically significant cognitive impairment affected all subtypes at follow-up, but its severity did not differ by subtype (3-month, p = 0.26; 12-month, p = 0.80)., Interpretation: The four data-derived delirium subtypes identified in this study should now be validated in independent cohorts, examined for differential treatment effects in trials, and inform mechanistic work evaluating treatment targets., Funding: National Institutes of Health (T32HL007820, R01AG027472)., Competing Interests: Declaration of interests Kelly Potter acknowledges support from the National Institutes of Health (NIH). Jason Kennedy acknowledges support from the NIH. Niall Prendergast received funding from the NIH and receives authorship royalties from McGraw-Hill. Chukwudi Onyemekwu acknowledges support from the NIH. Wes Ely reports work with Eli Lily as an unfunded investigator on COVID-19 studies with Baricitinib and acknowledges VA and NIH grant support. Christopher Seymour receives research funding from the NIH, receives personal fees from Inotrem, Beckman–Coulter, and Octapharma, and is an Associate Editor for JAMA. Timothy Girard receives research funding from the NIH, the Department of Defense, and Ceribell and served previously on an advisory board for Lungpacer Medical Inc., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation., Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU., Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021., Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days., Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle., Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration., Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation., Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

Purpose: We sought to determine the correlation between the Numeric Rating Scale (NRS) and Critical-Care Pain Observation Tool (CPOT) to determine whether clinical factors modified the relationship between NRS and CPOT assessments., Materials and Methods: We included nonventilated adults admitted to the MICU or SICU who could self-report pain and had at least 3 paired NRS and CPOT assessments. We performed Spearman correlation to assess overall correlation and performed proportional odds logistic regression to evaluate whether the relationship between NRS and CPOT assessments was modified by clinical factors., Results: Nursing staff performed NRS and CPOT assessments every 4 h in 1302 patients, leading to 61,142 matched assessments. We found that the NRS and CPOT have a Spearman correlation coefficient of 0.56 and an intraclass correlation coefficient of 0.32 in intensive care unit patients. Factors that modified the relationship between the NRS and CPOT included the presence of delirium ( P  < .001) and lower mean daily Richmond Agitation Sedation Scale (<0.001)., Conclusions: The correlation coefficient between the NRS and the CPOT was found to be 0.56. The presence of delirium, decreased level of arousal, modified the relationship between the NRS and CPOT. Self-reported and behavioral pain assessments cannot be used interchangeably in critically ill adults., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Ely received honoraria for nonpromotional speaking from Hospira Inc. Dr Ely and Hughes have received research grant from Dr Franz Kohler Chemie GMBH. Dr Hughes is a consultant for Sedana Medical. Keywords: Pain, Critical Care Pain Observation Tool, Numeric Rating Scale. Dr Stollings, Dr Rumbaugh, Ms. Wang, and Dr Hayhurst have nothing to disclose.

Health care should address the holistic gap between health outcomes, spirituality, religion, and humanistic care to optimize patient care. Treating the whole person encompasses both physical and metaphysical elements. Patients want health care professionals to recognize their spiritual and religious preferences, because these matter in their approach to illness, coping, and long-term outcomes., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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.)

Objective: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients., Methods: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR)., Results: Of 207 patients (median age = 68 years, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24 hours after surgery (median change = 0.28, interquartile range [IQR] = -0.48 to 1.24, Wilcoxon p = 0.001). Preoperative to 24 hours postoperative change in CPAR was greater among patients who developed delirium versus those who did not (median [IQR] = 1.31 [0.004 to 2.34] vs 0.19 [-0.55 to 1.08], p = 0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24 hours postoperative change in CPAR was independently associated with delirium occurrence (per CPAR increase of 1, odds ratio = 1.30, 95% confidence interval [CI] = 1.03-1.63, p = 0.026) and increased hospital length of stay (incidence rate ratio = 1.15, 95% CI = 1.09-1.22, p < 0.001)., Interpretation: Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay. ANN NEUROL 2023;94:1024-1035., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Professional society guidelines recommend limiting the use of antipsychotics in older patients with postoperative delirium. How these recommendations affected the use of antipsychotics and other psychoactive drugs in the postoperative period has not been studied., Methods: This retrospective cohort study included patients 65 years or older without psychiatric diagnoses who underwent major surgery in community hospitals (CHs) and academic medical centers (AMCs) in the United States. The outcome was the rate of hospital days exposed to antipsychotics, antidepressants, antiepileptics, benzodiazepines, hypnotics, and selective alpha-2 receptor agonist dexmedetomidine in the postoperative period by hospital type., Results: The study included 4,098,431 surgical admissions from CHs (mean age 75.0 [standard deviation, 7.1] years; 50.8% female) during 2008-2018 and 2,310,529 surgical admissions from AMCs (75.0 [7.4] years; 49.4% female) during 2009-2018. In the intensive care unit (ICU) setting, the number of exposed days per 1000 hospital-days declined for haloperidol (CHs: 33-21 days [p < 0.01]; AMCs: 24-15 days [p < 0.01]) and benzodiazepines (CHs: 261-136 days [p < 0.01]; AMCs: 150-77 days [p < 0.01]). The use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine increased, while hypnotic use varied by the hospital type. In the non-ICU setting, the rate declined for haloperidol in CHs but not in AMCs (CHs: 10-6 days [p < 0.01]; AMCs: 4-3 days [p = 0.52]) and for benzodiazepines in both settings (CHs: 126-56 days [p < 0.01]; AMCs: 30-27 days [p < 0.01]). The use of antiepileptics and antidepressants increased, while the use of atypical antipsychotics and hypnotics varied by the hospital type., Conclusions: The use of haloperidol and benzodiazepines in the postoperative period declined at both CHs and AMCs. These trends coincided with the increasing use of other psychoactive drugs., (© 2023 The American Geriatrics Society.)

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA-potentially capable of being translated to produce viral proteins-persist in tissue as a 'reservoir'. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated., (© 2023. Springer Nature America, Inc.)

Background: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months., Methods: This 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., Findings: Two 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)., Conclusion: Potentially 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)., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time., Objective: To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery., Design: Retrospective cohort study., Setting: U.S. hospitals in the Premier Healthcare Database., Patients: 17 115 patients aged 65 years and older without psychiatric disorders who were prescribed an oral antipsychotic drug after major surgery from 2009 to 2018., Interventions: Haloperidol (≤4 mg on the day of initiation), olanzapine (≤10 mg), quetiapine (≤150 mg), and risperidone (≤4 mg)., Measurements: The risk ratios (RRs) for in-hospital death, cardiac arrhythmia events, pneumonia, and stroke or transient ischemic attack (TIA) were estimated after propensity score overlap weighting., Results: The weighted population had a mean age of 79.6 years, was 60.5% female, and had in-hospital death of 3.1%. Among the 4 antipsychotics, quetiapine was the most prescribed (53.0% of total exposure). There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%, reference group), olanzapine (2.8%; RR, 0.74 [95% CI, 0.42 to 1.27]), quetiapine (2.6%; RR, 0.70 [CI, 0.47 to 1.04]), and risperidone (3.3%; RR, 0.90 [CI, 0.53 to 1.41]). The risk for nonfatal clinical events ranged from 2.0% to 2.6% for a cardiac arrhythmia event, 4.2% to 4.6% for pneumonia, and 0.6% to 1.2% for stroke or TIA, with no statistically significant differences by treatment group., Limitation: Residual confounding by delirium severity; lack of untreated group; restriction to oral low-to-moderate dose treatment., Conclusion: These results suggest that atypical antipsychotics and haloperidol have similar rates of in-hospital adverse clinical events in older patients with postoperative delirium who receive an oral low-to-moderate dose antipsychotic drug., Primary Funding Source: National Institute on Aging., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3021.

Objectives: We examined whether preadmission history of depression is associated with less delirium/coma-free (DCF) days, worse 1-year depression severity and cognitive impairment., Design and Measurements: A health proxy reported history of depression. Separate models examined the effect of preadmission history of depression on: (a) intensive care unit (ICU) course, measured as DCF days; (b) depression symptom severity at 3 and 12 months, measured by the Beck Depression Inventory-II (BDI-II); and (c) cognitive performance at 3 and 12 months, measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) global score., Setting and Participants: Patients admitted to the medical/surgical ICU services were eligible., Results: Of 821 subjects eligible at enrollment, 261 (33%) had preadmission history of depression. After adjusting for covariates, preadmission history of depression was not associated with less DCF days (OR 0.78, 95% CI, 0.59-1.03 p = 0.077). A prior history of depression was associated with higher BDI-II scores at 3 and 12 months (3 months OR 2.15, 95% CI, 1.42-3.24 p = <0.001; 12 months OR 1.89, 95% CI, 1.24-2.87 p = 0.003). We did not observe an association between preadmission history of depression and cognitive performance at either 3 or 12 months (3 months beta coefficient -0.04, 95% CI, -2.70-2.62 p = 0.97; 12 months 1.5, 95% CI, -1.26-4.26 p = 0.28)., Conclusion: Patients with a depression history prior to ICU stay exhibit a greater severity of depressive symptoms in the year after hospitalization.

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity. In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID., Competing Interests: Declaration of interests EWE and SWR have submitted a grant proposal to study the effects of baricitinib on long COVID. The other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although delirium detection and prevention practices are recommended in critical care guidelines, there remains a persistent lack of effective delirium education for ICU providers. To address this knowledge-practice gap, we developed an "ICU Delirium Playbook" to educate providers on delirium detection (using the Confusion Assessment Method for the ICU) and prevention., Design: Building on our previous ICU Delirium Video Series, our interdisciplinary team developed a corresponding quiz to form a digital "ICU Delirium Playbook." Playbook content validity was evaluated by delirium experts, and face validity by an ICU nurse focus group. Additionally, focus group participants completed the quiz before and after video viewing. Remaining focus group concerns were evaluated in semi-structured follow-up interviews., Setting: Online validation survey, virtual focus group, and virtual interviews., Subjects: The validation group included six delirium experts in the fields of critical care, geriatrics, nursing, and ICU education. The face validation group included nine ICU nurses, three of whom participated in the semi-structured feedback interviews., Interventions: None., Measurements and Main Results: The 44-question quiz had excellent content validity (average scale-level content validity index [S-CVI] of individual items = 0.99, universal agreement S-CVI = 0.93, agreement κ ≥ 0.75, and clarity p ≥ 0.8). The focus group participants completed the Playbook in an average (sd) time of 53 (14) minutes, demonstrating significant improvements in pre-post quiz scores (74% vs 86%; p = 0.0009). Verbal feedback highlighted the conciseness, utility, and relevance of the Playbook, with all participants agreeing to deploy the digital education module in their ICUs., Conclusions: The ICU Delirium Playbook is a novel, first-of-its-kind asynchronous digital education tool aimed to standardize delirium detection and prevention practices. After a rigorous content and face validation process, the Playbook is now available for widespread use., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Brain dysfunction during critical illness (ie, delirium and coma) is extremely common, and its lasting effect has only become increasingly understood in the last two decades. Brain dysfunction in the intensive care unit (ICU) is an independent predictor of both increased mortality and long-term impairments in cognition among survivors. As critical care medicine has grown, important insights regarding brain dysfunction in the ICU have shaped our practice including the importance of light sedation and the avoidance of deliriogenic drugs such as benzodiazepines. Best practices are now strategically incorporated in targeted bundles of care like the ICU Liberation Campaign's ABCDEF Bundle., (Copyright © 2023 Elsevier Inc. All rights reserved.)