Search

Atrial fibrillation (AF) is a common arrhythmia encountered in acute and critical illness and is associated with poor short and long-term outcomes. Given the consequences of developing AF, research into prevention, prediction and treatment of this arrhythmia in the critically ill are of great potential benefit, however, study of AF in critically ill patients faces unique challenges, leading to a sparse evidence base to guide management in this population. Major obstacles to the study of AF in acute and critical illness include absence of a common definition, challenges in designing studies that capture complex etiology and assess causality, lack of a clear outcome set, difficulites in recruitment in acute environments with respect to timing, consent, and workflow, and failure to embed studies into clinical care platforms and capitalize on emerging technologies. Collaborative effort by researchers, clinicians, and stakeholders should be undertaken to address these challenges, both through interdisciplinary cooperation for the optimization of research efficiency and advocacy to advance the understanding of this common and complex arrhythmia, resulting in improved patient care and outcomes. The Symposium on Atrial Fibrillation in Acute and Critical Care was convened to address some of these challenges and propose potential solutions., (© 2024. The Author(s).)

Background: Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes., Methods: In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay., Ethics and Dissemination: This study has been approved by the Health Sciences Research Ethics Board at Queen's University. The results of this study will be actively disseminated through manuscript publication and conference presentations., Trial Registration Number: NCT05761613., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure., Design: A double-blind, randomized, placebo-controlled trial., Setting: Multicenter ICU study., Patients: Adults requiring invasive mechanical ventilation secondary to COVID-19., Intervention: Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation., Measurements and Main Results: The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio 2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao 2 /Fio 2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control ( p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% ( p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events., Conclusions: In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao 2 /Fio 2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology., Competing Interests: Dr. Muscedere is the scientific director for the Canadian Frailty Network and has received in-kind contributions of endotracheal tubes for a study of the prevention of ventilator-associated pneumonia from N8 Pharma. Dr. Boyd receives a stipend from Ontario Health-Trillium Gift of Life Network for his role as Regional Medical Lead and has received in-kind support from Edwards LifeSciences of cerebral oximeters for the Cerbral Oxygenation and Neurological Outcomes Following Critical Illness-2 study. The remaining authors have no disclosures or conflicts of interest relevant to this work., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose: Cerebral autoregulation (CA) is a mechanism that acts to maintain consistent cerebral perfusion across a range of blood pressures, and impaired CA is associated with delirium. Individualized CA-derived blood pressure targets are poorly characterized in critically ill patients and the association with intensive care unit (ICU) delirium is unknown. Our objectives were to characterize optimal mean arterial pressure (MAP opt ) ranges in critically ill adults without brain injury and determine whether deviations from these targets contribute to ICU delirium., Methods: We performed a retrospective cohort analysis of patients with shock of any etiology and/or respiratory failure requiring invasive mechanical ventilation, without a neurologic admitting diagnosis. Patients were screened daily for delirium. Cerebral oximetry and mean arterial pressure data were captured for the first 24 hr from enrolment., Results: Forty-two patients with invasive blood pressure monitoring data were analyzed. Optimal mean arterial pressure targets ranged from 55 to 100 mm Hg. Optimal mean arterial pressure values were not significantly different based on history of hypertension or delirium status, and delirium was not associated with deviations from MAP opt . Nevertheless, the majority (69%) of blood pressure targets exceeded the current 65 mm Hg Surviving Sepsis guidelines., Conclusion: We observed that MAP opt targets across patients were highly variable, but did not observe an association with the incidence of delirium. Studies designed to evaluate the impact on neurologic outcomes are needed to understand the association with individualized mean arterial pressure targets in the ICU., Study Registration: ClinicalTrials.gov (NCT02344043); first submitted 22 January 2015., (© 2023. Canadian Anesthesiologists' Society.)

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

The Society of Critical Care Medicine (SCCM) Reviewer Academy seeks to train and establish a community of trusted, reliable, and skilled peer reviewers with diverse backgrounds and interests to promote high-quality reviews for each of the SCCM journals. Goals of the Academy include building accessible resources to highlight qualities of excellent manuscript reviews; educating and mentoring a diverse group of healthcare professionals; and establishing and upholding standards for insightful and informative reviews. This manuscript will map the mission of the Reviewer Academy with a succinct summary of the importance of peer review, process of reviewing a manuscript, and the expected ethical standards of reviewers. We will equip readers to target concise, thoughtful feedback as peer reviewers, advance their understanding of the editorial process and inspire readers to integrate medical journalism into diverse professional careers., Competing Interests: Dr. Alexander has received funding from the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (R13HD104432), Food and Drug Administration (FP01029501), US Department of Defense (W81XWH2210301), and unrestricted grants from the Extracorporeal Life Support Organization (ELSO). Her institution received funding from Novartis (end-point adjudication committee PANORAMA-HF) and she serves as the ELSO Treasurer of the Board of Directors. Dr. Barreto received funding from Wolters-Kluwer. Dr. Morrow’s institution received funding from the Society of Critical Care Medicine (SCCM) for her role as Senior Associate Editor for Pediatric Critical Care Medicine, the National Research Foundation of Southern Africa, and EuroQual; she received funding from the Brazilian Physiotherapy Association. Dr. Mayer’s institution received funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (no. K23-AR079583); he received support for article research from the NIH. Dr. Lane-Fall’s institution receives funding from NIH (R01HL153735, P30AG059302, UM1HL088957, U01OD033246, R01HD105446, R01HD109229), Agency for Healthcare Research and Quality (K12HS026372), Patient-Centered Outcomes Research Institute (21106), and the American Heart Association (962544). She serves as the Vice President of the Anesthesia Patient Safety Foundation and is on the Board of Directors of the Foundation for Anesthesia Education and Research. Dr. Kudchadkar has received funding from NIH/NICHD (R01HD103811) and NIH/NIDDK (R01DK132348). Dr. Rech has received research funding from Spero Pharmaceuticals. Ms. Napolitano receives funding from NIH (1R44HD105552, 1R21HD103927-01A1, 1R01HD106996) and FDA (5P50FD006427) and also has research/consulting relationships with Drager, Philips/Respironics, Timpel, Actuated Medical, and Vero-Biotech. Dr. Sorce disclosed that she is an SCCM Executive Board Member. Dr. Tasker is the Editor-in-Chief for Pediatric Critical Care Medicine. Dr. Buchman is Editor-in-Chief for Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Acute kidney injury (AKI) resulting in kidney replacement therapy is rising among critically ill adults. Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation (rSO 2 ) may be a contributing factor., Objective: To assess the feasibility of testing the association between intradialytic rSO 2 and acute and long-term neurological outcomes., Design: Longitudinal observational study., Setting and Participants: We enrolled patients initiating continuous kidney replacement therapy or intermittent hemodialysis in the Kingston Health Sciences Centre (KHSC) Intensive Care Unit (ICU)., Measurements and Methods: rSO 2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging., Results: Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSO 2 /vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors., Limitations: Enrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes., Conclusion: rSO 2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.H.S. is cofounder and CSO of Kinarm (Kingston, Ontario, Canada), which commercializes the Kinarm End-Point Lab robotic technology used in the present study. S.A.S. has received speaking fees from Baxter Canada. N.A.J., R.M.H., A.G.D., P.A.N., B.Y.M.K., D.M.M., J.M., and J.G.B. have no conflicts of interest to declare., (© The Author(s) 2023.)

Clinical research must balance the need for ambitious recruitment with protecting participants' autonomy; a requirement of which is informed consent. Despite efforts to improve the informed consent process, participants are seldom provided sufficient information regarding research, hindering their ability to make informed decisions. These issues are particularly pervasive among patients experiencing acute illness or neurological impairment, both of which may impede their capacity to provide consent. There is a critical need to understand the components, requirements, and methods of obtaining true informed consent to achieve the vast numbers required for meaningful research. This paper provides a comprehensive review of the tenets underlying informed consent in research, including the assessment of capacity to consent, considerations for patients unable to consent, when to seek consent from substitute decision-makers, and consent under special circumstances. Various methods for obtaining informed consent are addressed, along with strategies for balancing recruitment and consent., (© The Author(s) 2023. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves., Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic., Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated ( n = 19/237) than unvaccinated hospitalized patients ( n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves., Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave., Competing Interests: Competing interests: Keith Walley reports receiving a Canadian Institutes of Health Research (CIHR) Foundation grant, paid to the University of British Columbia. Dr. Walley has also participated on data safety monitoring boards (unpaid) for Northern Therapeutics and the Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome (CIRCA-19) trial. Allison McGeer reports receiving grants from Sanofi, Merck and Pfizer (paid to institution), as well as payment or honoraria from AstraZeneca, Merck, Biogen and Moderna. Dr. McGeer has also received travel support from Moderna and has participated on a data safety monitoring or advisory board for Pfizer, GlaxoSmithKline, Moderna, Medicago, Janssen, AstraZeneca, Novavax and Sanofi., (© 2023 CMA Impact Inc. or its licensors.)

Objective: Interindividual variability in the clinical progression of COVID-19 may be explained by host genetics. Emerging literature supports a potential inherited predisposition to severe forms of COVID-19. Demographic and inflammatory characteristics of COVID-19 suggest that acquired hematologic mutations leading to clonal hematopoiesis (CH) may further increase vulnerability to adverse sequelae. This review summarizes the available literature examining genetic predispositions to severe COVID-19 and describes how these findings could eventually be used to improve its clinical management., Data Sources: A PubMed literature search was performed., Study Selection: Studies examining the significance of inherited genetic variation or acquired CH mutations in severe COVID-19 were selected for inclusion., Data Extraction: Relevant genetic association data and aspects of study design were qualitatively assessed and narratively synthesized., Data Synthesis: Genetic variants affecting inflammatory responses may increase susceptibility to severe COVID-19. Genome-wide association studies and candidate gene approaches have identified a list of inherited mutations, which likely alter cytokine and interferon secretion, and lung-specific mechanisms of immunity in COVID-19. The potential role of CH in COVID-19 is more uncertain at present; however, the available evidence suggests that the various types of acquired mutations and their differential influence on immune cell function must be carefully considered., Conclusions: The current literature supports the hypothesis that host genetic factors affect vulnerability to severe COVID-19. Further research is required to confirm the full scope of relevant variants and the causal mechanisms underlying these associations. Clinical approaches, which consider the genetic basis of interindividual variability in COVID-19 and potentially other causes of critical illness, could optimize hospital resource allocation, predict responsiveness to treatment, identify more efficacious drug targets, and ultimately improve outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Introduction: Sepsis is a result of initial over-activation of the immune system in response to an infection or trauma that results in reduced blood flow and life-threatening end-organ damage, followed by suppression of the immune system that prevents proper clearance of the infection or trauma. Because of this, therapies that not only limit the activation of the immune system early on, but also improve blood flow to crucial organs and reactivate the immune system in late-stage sepsis, may be effective treatments. The tyrosine kinase FES may fulfill this role. FES is present in immune cells and serves to limit immune system activation. We hypothesize that by enhancing FES in early sepsis and inhibiting its effects in late sepsis, the severity and outcome of septic illness can be improved., Methods and Analysis: In vitro and in vivo modeling will be performed to determine the degree of inflammatory signaling, cytokine production, and neutrophil extracellular trap (NET) formation that occurs in wild-type (WT) and FES knockout ( FES -/- ) mice. Clinically available treatments known to enhance or inhibit FES expression (lorlatinib and decitabine, respectively), will be used to explore the impact of early vs. late FES modulation on outcomes in WT mice. Bioinformatic analysis will be performed to examine FES expression levels in RNA transcriptomic data from sepsis patient cohorts, and correlate FES expression data with clinical outcomes (diagnosis of sepsis, illness severity, hospital length-of-stay)., Ethics and Dissemination: Ethics approval pending from the Queen's University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board. Results will be disseminated through scientific publications and through lay summaries to patients and families., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laight, Jawa, Tyryshkin, Maslove, Boyd and Greer.)

Patients with critical neurological illness are diverse. As a result of the heterogeneity of this patient population, standardized approaches to patient management might not confer benefit. A precision medicine approach to neurocritical care is therefore urgently needed to improve our understanding of neurocritical illness and the care provided to this vulnerable cohort. Research designs and approaches based on Bayesian models have the potential to meet this need, as they are specifically designed to evolve with emerging evidence. This adaptability provides a benefit over the popular frequentist statistical approach, as it provides a way of adjusting hypotheses and trial procedures to maximize efficacy. This review summarizes the current state of knowledge on Bayes' theorem, and its potential applications to the field of neurocritical care. We review the basic principles underlying Bayes' theorem, compare the use of Bayesian versus frequentist statistics in medicine, and discuss the relevance of Bayesian statistics to the field of neuroscience and to clinical research. Finally, we explore the potential benefits of employing Bayesian methods within the field of neurocritical care as a steppingstone toward implementing precision medicine approaches to improve patient outcomes for complex, heterogeneous disorders., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the intensive care unit and is associated with increased morbidity and mortality. New-onset atrial fibrillation (NOAF) is often initially paroxysmal and fleeting, making it difficult to diagnose, and therefore difficult to understand the true burden of disease. Automated algorithms to detect AF in the ICU have been advocated as a means to better quantify its true burden., Results: We used a publicly available 12-lead ECG dataset to train a deep learning model for the classification of AF. We then conducted an external independent validation of the model using continuous telemetry data from 984 critically ill patients collected in our institutional database. Performance metrics were stratified by signal quality, classified as either clean or noisy. The deep learning model was able to classify AF with an overall sensitivity of 84%, specificity of 89%, positive predictive value (PPV) of 55%, and negative predictive value of 97%. Performance was improved in clean data as compared to noisy data, most notably with respect to PPV and specificity., Conclusions: This model demonstrates that computational detection of AF is currently feasible and effective. This approach stands to improve the efficiency of retrospective and prospective research into AF in the ICU by automating AF detection, and enabling precise quantification of overall AF burden., (© 2023. The Author(s).)

High-frequency data streams of vital signs may be used to generate individualized hemodynamic targets for critically ill patients. Central to this precision medicine approach to resuscitation is our ability to screen these data streams for errors and artifacts. However, there is no consensus on the best method for data cleaning. Our goal was to determine whether an error-checking algorithm developed for intraoperative use could be applied to high volumes of arterial line data in an ICU population., Design: Multicenter observational study., Setting: ICUs across Ontario, Canada., Patients: Nested cohort of ICU patients with shock and/or respiratory failure requiring invasive mechanical ventilation., Interventions: High-frequency blood pressure data was analyzed. Systolic, diastolic, and mean arterial pressure minute averages were calculated. For manual analysis, a trained researcher retrospectively reviewed mean arterial pressure data, removing values that were deemed nonphysiological. The algorithm was implemented and identified artifactual data., Measurements and Main Results: Arterial line data was extracted from 15 patients. A trained researcher manually reviewed 40,798 minute-by-minute data points, then subsequently analyzed them with the algorithm. Manual review resulted in the identification of 119 artifacts (0.29%). The optimized algorithm identified 116 (97%) of these artifacts. Five hundred thirty-seven data points were erroneously removed or modified. Compared with manual review, the modified algorithm incorporating absolute thresholds of greater than 30 and less than 200 mm Hg had 97.5% sensitivity, 98.7% specificity, and a Matthew correlation coefficient of 0.41., Conclusions: The error-checking algorithm had high sensitivity and specificity in detecting arterial line blood pressure artifacts compared with manual data cleaning. Given the growing use of large datasets and machine learning in critical care research, methods to validate the quality of high-frequency data is important to optimize algorithm performance and prevent spurious associations based on artifactual data., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction., Methods: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28., Results: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event., Conclusions: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.)., (Copyright © 2022 Massachusetts Medical Society.)

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside., (© 2022. Springer Nature America, Inc.)

Background: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor., Objective: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database., Methods: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses., Results: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status., Conclusions: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase., International Registered Report Identifier (irrid): DERR1-10.2196/36261., (©Neill KJ Adhikari, Ruxandra Pinto, Andrew G Day, Marie-Hélène Masse, Julie Ménard, Sheila Sprague, Djillali Annane, Yaseen M Arabi, Marie-Claude Battista, Dian Cohen, Deborah J Cook, Gordon H Guyatt, Daren K Heyland, Salmaan Kanji, Shay P McGuinness, Rachael L Parke, Bharath Kumar Tirupakuzhi Vijayaraghavan, Emmanuel Charbonney, Michaël Chassé, Lorenzo Del Sorbo, Demetrios James Kutsogiannis, François Lauzier, Rémi Leblanc, David M Maslove, Sangeeta Mehta, Armand Mekontso Dessap, Tina S Mele, Bram Rochwerg, Oleksa G Rewa, Jason Shahin, Pawel Twardowski, Paul Jeffrey Young, François Lamontagne, LOVIT Investigators. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.05.2022.)

Patients admitted to the ICU with critical COVID-19 often require prolonged periods of mechanical ventilation. Difficulty weaning, lack of progress, and clinical deterioration are commonly encountered. These conditions should prompt a thorough evaluation for persistent or untreated manifestations of COVID-19, as well as complications from COVID-19 and its various treatments. Inflammation may persist and lead to fibroproliferative changes in the lungs. Infectious complications may arise including bacterial superinfection in the earlier stages of disease. Use of immunosuppressants may lead to the dissemination of latent infections, and to opportunistic infections. Venous thromboembolic disease is common, as are certain neurologic manifestations of COVID-19 including delirium and stroke. High levels of ventilatory support may lead to ventilator-induced injury to the lungs and diaphragm. We present diagnostic and therapeutic considerations for the mechanically ventilated patient with COVID-19 who shows persistent or worsening signs of critical illness, and we offer an approach to treating this complex but common scenario., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Importance: Prognostication following ICU admission can often be determined based on known risk factors, including demographics and illness severity; however, little is known about outcomes of patients deemed to be "low-risk" at the time of hospital admission who subsequently are admitted to the ICU., Objectives: The objectives of this study were to determine the characteristics, outcomes, and costs for patients requiring ICU admission despite having lower predicted mortality when they were admitted to the hospital., Design Setting and Participants: In this historical cohort study, we used a prospectively maintained ICU registry that included all ICU admissions to The Ottawa Hospital for patients 18 years or older from January 2011 to December 2016. We classified patients as low-risk using the Hospital-patient 1-year Mortality Risk at admission score, a hospital admission score validated to predict 1-year mortality., Main Outcomes and Measures: The primary outcome was inhospital mortality. Secondary outcomes included adverse events, resource utilization, and costs., Results: Of the 17,173 total ICU patients, 3,445 (20.1%) were classified as low-risk at hospital admission. Low-risk patients were younger (48.7 vs 67.5 yr; p < 0.001) and had a lower Multiple Organ Dysfunction Score (2.37 vs 4.14; p < 0.001). Mortality for low-risk patients was significantly lower than for non-low-risk patients (4.1% vs 25.4%; p < 0.001). For low-risk patients, multivariable logistic regression showed mortality was independently associated with older age (odds ratio, 1.02 per 1 yr; 95% CI, 1.00-1.03 per 1 yr), Multiple Organ Dysfunction Score (odds ratio, 1.42 per 1 point; 95% CI, 1.31-1.54 per 1 point), fluid management adverse events (odds ratio, 2.84; 95% CI, 1.29-6.25), hospital-acquired infections (odds ratio, 1.60; 95% CI, 1.02-2.51), and mechanical ventilation (odds ratio, 1.98; 95% CI, 1.20-3.26)., Conclusions and Relevance: Despite their robust premorbid status, low-risk patients admitted to the ICU had significant inhospital mortality. Fluid management adverse events, hospital-associated infections, multiple organ dysfunction, and mechanical ventilation are important prognostic factors for low-risk patients., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Initiation of acute kidney replacement therapy (KRT) is common in critically ill adults admitted to the intensive care unit (ICU), and associated with increased morbidity and mortality. KRT has been linked to poor neurocognitive outcomes, leading to reduced quality of life and increased utilisation of healthcare resources. Adults on dialysis in the ICU may be particularly at risk of neurocognitive impairment, as survivors of critical illness are already predisposed to developing cerebrovascular disease and cognitive dysfunction long-term relative to healthy controls. Regional cerebral oxygen saturation may provide a critical early marker of long-term neurocognitive impairment in this population. This study aims to understand cerebral oxygenation in patients undergoing KRT (continuous or intermittent) in the ICU. These findings will be correlated with long-term cognitive and functional outcomes, and structural brain pathology., Methods and Analysis: 108 patients scheduled to undergo treatment for acute kidney injury with KRT in the Kingston Health Sciences Centre ICU will be recruited into this prospective observational study. Enrolled patients will be assessed with intradialytic cerebral oximetry using near infrared spectroscopy. Delirium will be assessed daily with the Confusion Assessment Method-ICU (CAM-ICU) and severity quantified as cumulative CAM-ICU-7 scores. Neurocognitive impairment will be assessed at 3 and 12 months after hospital discharge using the Kinarm and Repeatable Battery for the Assessment of Neuropsychological Status. Structural brain pathology on MRI will also be measured at the same timepoints. Driving safety, adverse events and medication adherence will be assessed at 12 months to evaluate the impact of neurocognitive impairment on functional outcomes., Ethics and Dissemination: This study is approved by the Queen's University Health Sciences/Affiliated Teaching Hospitals Research Ethics Board (DMED-2424-20). Results will be presented at critical care conferences, and a lay summary will be provided to patients in their preferred format., Trial Registration Number: NCT04722939., Competing Interests: Competing interests: SHS is cofounder and CSO of Kinarm that commercialises the Kinarm robotic technology used in the present study. NAJ, RMH, SAS, AGD, PAN, BYMK, DMM, JM and JGB have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Decision making about discharge destination for critically ill patients is a highly subjective and multidisciplinary process, heavily reliant on the ICU care team, patients and their caregivers' preferences, resource demand, staffing, and bed capacity. Timely identification of discharge disposition can be useful in care planning, and as a surrogate for functional status outcomes following critical illness. Although prior research has proposed methods to predict discharge destination in a critical care setting, they are limited in scope and in the generalizability of their findings. We proposed and implemented different machine learning architectures to determine the efficacy of the Acute Physiology and Chronic Health Evaluation (APACHE) IV score as well as the patient characteristics that comprise it to predict the discharge destination for critically ill patients within 24 hours of ICU admission. We conducted a retrospective study of ICU admissions within the eICU Collaborative Research Database (eICU-CRD) populated with de-identified clinical data from adult patients admitted to an ICU between 2014 and 2015. Machine learning models were developed to predict four discharge categories: death, home, nursing facility, and rehabilitation. These models were trained and tested on 115,248 unique ICU admissions. To mitigate class imbalance, we used synthetic minority over-sampling techniques. Hierarchical and ensemble classifiers were used to further study the impact of imbalanced testing set on the performance of our predictive models. Amongst all of the tested models, XGBoost provided the best discrimination performance with an area under the receiver operating characteristic curve of 90% (recall: 71%, F1: 70%). Our findings indicate that the variables used in the APACHE IV model for estimating patient severity of illness are better predictors of hospital discharge destination than the APACHE IV score alone. Incorporating these models into clinical decision support systems may assist patients, caregivers, and the ICU team to begin disposition planning as early as possible during the hospitalization.

Background: Critical illness has been suggested as a sentinel event for frailty development in at-risk older adults. Frail critical illness survivors are affected by increased adverse health outcomes, but monitoring the recovery after intensive care unit (ICU) discharge is challenging. Clinicians and funders of health care systems envision an increased role of wearable devices in monitoring clinically relevant measures, as sensor technology is advancing rapidly. The use of wearable devices has also generated great interest among older patients, and they are the fastest growing group of consumer-grade wearable device users. Recent research studies indicate that consumer-grade wearable devices offer the possibility of measuring frailty., Objective: This study aims to examine the data collected from wearable devices for the progression of frailty among critical illness survivors., Methods: An observational study was conducted with 12 older survivors of critical illness from Kingston General Hospital in Canada. Frailty was measured using the Clinical Frailty Scale (CFS) at ICU admission, hospital discharge, and 4-week follow-up. A wearable device was worn between hospital discharge and 4-week follow-up. The wearable device collected data on step count, physical activity, sleep, and heart rate (HR). Patient assessments were reviewed, including the severity of illness, cognition level, delirium, activities of daily living, and comorbidity., Results: The CFS scores increased significantly following critical illness compared with the pre-ICU frailty level (P=.02; d=-0.53). Survivors who were frail over the 4-week follow-up period had significantly lower daily step counts than survivors who were not frail (P=.02; d=1.81). There was no difference in sleep and HR measures. Daily step count was strongly correlated with the CFS at 4-week follow-up (r=-0.72; P=.04). The average HR was strongly correlated with the CFS at hospital discharge (r=-0.72; P=.046). The HR SD was strongly correlated (r=0.78; P=.02) with the change in CFS from ICU admission to 4-week follow-up. No association was found between the CFS and sleep measures. The pattern of increasing step count over the 4-week follow-up period was correlated with worsening of frailty (r=.62; P=.03)., Conclusions: This study demonstrated an association between frailty and data generated from a consumer-grade wearable device. Daily step count and HR showed a strong association with the frailty progression of the survivors of critical illness over time. Understanding this association could unlock a new avenue for clinicians to monitor and identify a vulnerable subset of the older adult population that might benefit from an early intervention., (©Ben Kim, Miranda Hunt, John Muscedere, David M Maslove, Joon Lee. Originally published in JMIR Aging (http://aging.jmir.org), 23.02.2021.)

Background: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied., Methods: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity., Results: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients., Conclusions: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.)., (Copyright © 2021 Massachusetts Medical Society.)

Objectives: The eICU Collaborative Research Database is a publicly available repository of granular data from more than 200,000 ICU admissions. The quantity and variety of its entries hold promise for observational critical care research. We sought to understand better the data available within this resource to guide its future use., Design: We conducted a descriptive analysis of the eICU Collaborative Research Database, including patient, practitioner, and hospital characteristics. We investigated the completeness of demographic and hospital data, as well as those values required to calculate an Acute Physiology and Chronic Health Evaluation score. We also assessed the rates of ventilation, intubation, and dialysis, and looked for potential errors in the vital sign data., Setting: American ICUs that participated in the Philips Healthcare eICU program between 2014 and 2015., Patients: A total of 139,367 individuals who were admitted to one of the 335 participating ICUs between 2014 and 2015., Interventions: None., Measurements and Main Results: Most encounters were from small- and medium-sized hospitals, and managed by nonintensivists. The median ICU length of stay was 1.57 days (interquartile range, 0.82-2.97 d). The median Acute Physiology and Chronic Health Evaluation IV-predicted ICU mortality was 2.2%, with an observed mortality of 5.4%. Rates of ventilation (20-33%), intubation (15-24%), and dialysis (3-5%) varied according to the query method used. Most vital sign readings fell into realistic ranges, with manually curated data less likely to contain implausible results than automatically entered data., Conclusions: Data in the eICU Collaborative Research Database are for the most part complete and plausible. Some ambiguity exists in determining which encounters are associated with various interventions, most notably mechanical ventilation. Caution is warranted in extrapolating findings from the eICU Collaborative Research Database to larger ICUs with higher acuity.

Introduction: Immunological dysfunction is common in critically ill patients but its clinical significance and the optimal method to measure it are unknown. The level of tumor necrosis factor alpha (TNF-α) after ex-vivo whole blood stimulation with lipopolysaccharide (LPS) has been proposed as a possible method to quantify immunological function. We hypothesized that in a cohort of critically ill patients, those with a lower post-stimulation TNF-α level would have increased rates of nosocomial infections (NIs) and worse clinical outcomes., Methods: A secondary analysis of a phase 2 randomized, multi-centre, double-blinded placebo-controlled trial. As there was no difference between treatment and control arms in outcomes and NI rate, all the patients were analyzed as one cohort. On enrolment, day 4, 7, and weekly until day 28, whole blood was incubated with LPS ex-vivo and subsequent TNF-α level was measured. Patients were grouped in tertiles according to delta and peak TNF-α level. The primary outcome was the association between NIs and tertiles of TNF-α level post LPS stimulation; secondary outcomes included ICU and 90-day mortality, and ICU and hospital length of stay., Results: Data was available for 201 patients. Neither the post LPS stimulation delta TNF-α group nor the peak TNF-α post-stimulation group were associated with the development of NIs or clinical outcomes. Patients in the highest tertile for post LPS stimulation delta TNF-α compared to the lowest tertile were younger [61.1 years ± 15.7 vs. 68.6 years ± 12.8 standard deviations (SD) in the lowest tertile], had lower acuity of illness (APACHE II 25.0 ± 9.7 vs. 26.7 ± 6.1) and had lower baseline TNF-α (9.9 pg/mL ± 19.0 vs. 31.0 pg/mL ± 68.5). When grouped according to peak post-stimulation TNF-α levels, patients in the highest tertile had higher serum TNF-α at baseline (21.3 pg/mL ± 66.7 compared to 6.5 pg/mL ± 9.0 in the lowest tertile)., Conclusion: In this prospective multicenter study, ex-vivo stimulated TNF-α level was not associated with the occurrence of NIs or clinical outcomes. Further study is required to better ascertain whether TNF levels and ex-vivo stimulation can be used to characterize immune function in critical illness and if other assays might be better suited to this task.

Mortality has long been used as a primary end point for randomized controlled trials in critical care. Recently, a plurality of trials targeting mortality end points as their primary outcome has failed to detect a difference between study arms. While there are a number of reasons for the preponderance of such neutral trials, the use of mortality as an outcome is one important consideration. We explore some of the reasons why such trials may be biased toward a neutral result, as well as reasons to consider alternative end points that are better coupled to the expected therapeutic effect. We also discuss to what extent mortality as a binary outcome is patient-important in the ICU., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

Delirium is common during critical illness and is associated with morbidity and mortality, but its pathophysiology is unknown. We tested whether dysfunctional cerebral autoregulation (CA) contributes to the development of delirium. Adult patients ( n  = 40) with respiratory failure and/or shock were prospectively enrolled. Continuous recordings of regional cerebral oxygen saturation (rSO 2 ) were obtained by near-infrared spectroscopy (NIRS) during the first 72 h of intensive care unit (ICU) admission. CA function was estimated by the cerebral oximetry index (COx), which is the time-varying correlation between rSO 2 and mean arterial pressure (MAP). Delirium was assessed daily. The median ICU stay was seven days (IQR 4-13). Twenty-four patients (60%) screened positive for delirium on at least one day during their stay. Taking positive COx values to reflect periods of CA dysfunction, we found that the cumulative duration of CA dysfunction during the first one to three days in the ICU was significantly associated with the subsequent development of delirium. Additionally, we assessed two alternative methods for estimating optimal MAP targets in individual patients. In summary, early disturbances in CA may contribute to delirium, and NIRS-derived rSO2 may be used to identify individual perfusion targets in critically ill patients.

Objectives: Randomized controlled trials in the ICU often fail to show differences in endpoints between groups. We sought to explore reasons for this at a molecular level by analyzing transcriptomic data from a recent negative trial. Our objectives were to determine if randomization successfully balanced transcriptomic features between groups, to assess transcriptomic heterogeneity among the study subjects included, and to determine if the study drug had any effect at the gene expression level., Design: Bioinformatics analysis of transcriptomic and clinical data collected in the course of a randomized controlled trial., Setting: Tertiary academic mixed medical-surgical ICU., Patients: Adult, critically ill patients expected to require invasive mechanical ventilation more than 48 hours., Interventions: Lactoferrin or placebo delivered enterally and via an oral swab for up to 28 days., Measurements and Main Results: We found no major imbalances in transcriptomic features between groups. Unsupervised analysis did not reveal distinct clusters among patients at the time of enrollment. There were marked differences in gene expression between early and later time points. Patients in the lactoferrin group showed changes in the expression of genes associated with immune pathways known to be associated with lactoferrin., Conclusions: In this clinical trial, transcriptomic data provided a useful complement to clinical data, suggesting that the reasons for the negative result were less likely related to the biological efficacy of the study drug, and may instead have been related to poor sensitivity of the clinical outcomes. In larger studies, transcriptomics may also prove useful in predicting response to treatment.

Introduction: Survivors of critical illness frequently exhibit acute and chronic neurological complications. The underlying aetiology of this dysfunction remains unknown but may be associated with cerebral ischaemia. This study will use near-infrared spectroscopy to non-invasively quantify regional cerebral oxygenation (rSO 2 ) to assess the association between poor rSO 2 during the first 72 hours of critical illness with delirium severity, as well as long-term sensorimotor and cognitive impairment among intensive care unit (ICU) survivors. Further, the physiological determinants of rSO 2 will be examined., Methods and Analysis: This multicentre prospective observational study will consider adult patients (≥18 years old) eligible for enrolment if within 24 hours of ICU admission, they require mechanical ventilation and/or vasopressor support. For 72 hours, rSO 2 will be continuously recorded, while vital signs (eg, heart rate) and peripheral oxygenation saturation will be concurrently captured with data monitoring software. Arterial and central venous gases will be sampled every 12 hours for the 72 hours recording period and will include: pH, PaO2, PaCO2, and haemoglobin concentration. Participants will be screened daily for delirium with the confusion assessment method (CAM)-ICU, whereas the brief-CAM will be used on the ward. At 3 and 12 months post-ICU discharge, neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and KINARM sensorimotor and cognitive robot-based behavioural tasks., Ethics and Dissemination: The study protocol has been approved in Ontario by a central research ethics board (Clinical Trials Ontario); non-Ontario sites will obtain local ethics approval. The study will be conducted under the guidance of the Canadian Critical Care Trials Group (CCCTG) and the results of this study will be presented at national meetings of the CCCTG for internal peer review. Results will also be presented at national/international scientific conferences. On completion, the study findings will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03141619., Competing Interests: Competing interests: JM is the scientific director of the Canadian Frailty Network. SHS is the cofounder of BKIN Technologies, the manufacturer of the KINARM device. IB receives a stipend from the Trillium Gift of Life Network to support his role as a Regional Medical Lead. NO received funding from the Academic Medical Organization of Southwestern Ontario. MS receives a stipend from the Trillium Gift of Life Network to support his role as a Hospital Donation Physician. DG is funded through a Health-Professional Investigator Award from the Michael Smith Foundation for Health Research. JGB receives a stipend from the Trillium Gift of Life Network to support his role as a Regional Medical Lead., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To maintain adequate oxygen delivery to tissue, resuscitation of critically ill patients is guided by assessing surrogate markers of perfusion. As there is no direct indicator of cerebral perfusion used in routine critical care, identifying an accurate strategy to monitor brain perfusion is paramount. Near-infrared spectroscopy (NIRS) is a non-invasive technique to quantify regional cerebral oxygenation (rSO 2 ) that has been used for decades during cardiac surgery which has led to targeted algorithms to optimize rSO 2 being developed. However, these targeted algorithms do not exist during critical care, as the physiological determinants of rSO 2 during critical illness remain poorly understood., Materials and Methods: This prospective observational study was an exploratory analysis of a nested cohort of patients within the CONFOCAL study ( NCT02344043 ) who received high-fidelity vital sign monitoring. Adult patients (≥ 18 years) admitted < 24 h to a medical/surgical intensive care unit were eligible if they had shock and/or required mechanical ventilation. Patients underwent rSO 2 monitoring with the FORESIGHT oximeter for 24 h, vital signs were concurrently recorded, and clinically ordered arterial blood gas samples and hemoglobin concentration were also documented. Simultaneous multiple linear regression was performed using all available predictors, followed by model selection using the corrected Akaike information criterion (AICc)., Results: Our simultaneous multivariate model included age, heart rate, arterial oxygen saturation, mean arterial pressure, pH, partial pressure of oxygen, partial pressure of carbon dioxide (PaCO 2 ), and hemoglobin concentration. This model accounted for a significant proportion of variance in rSO 2 (R 2  = 0.58, p < 0.01) and was significantly associated with PaCO 2 (p < 0.05) and hemoglobin concentration (p < 0.01). Our selected regression model using AICc accounted for a significant proportion of variance in rSO 2 (R 2  = 0.54, p < 0.01) and was significantly related to age (p < 0.05), PaCO 2 (p < 0.01), hemoglobin (p < 0.01), and heart rate (p < 0.05)., Conclusions: Known and established physiological determinants of oxygen delivery accounted for a significant proportion of the rSO 2 signal, which provides evidence that NIRS is a viable modality to assess cerebral oxygenation in critically ill adults. Further elucidation of the determinants of rSO 2 has the potential to develop a NIRS-guided resuscitation algorithm during critical illness., Trial Registration: This trial is registered on clinicaltrials.gov (Identifier: NCT02344043 ), retrospectively registered January 8, 2015.

Purpose: Gene expression diagnostics have been proposed to identify critically ill patients with sepsis. Three expression-based scores have been developed, but have not been compared in a prospective validation. We sought to validate these scores using an independent dataset and analysis., Methods: We generated gene expression profiles from 61 critically ill patients. We validated the performance of 3 expression-based sepsis scores including 1) the Sepsis MetaScore (SMS); 2) the SeptiCyte™ Lab; and 3) the FAIM3:PLAC8 ratio. Sepsis was identified as the presence of definite, probable, or possible infection in the setting of organ dysfunction (SOFA score ≥ 2)., Results: For all 3 models, scores were significantly different between patients with and without sepsis. Discrimination was highest for the SMS (area under the receiver operating characteristics curve [AUROC 0.80 [95% CI 0.67-0.92]), with greater confidence in the presence of infection resulting in better model performance (max AUROC 0.93 [0.87-1.0])., Conclusions: All three scores distinguished septic from non-septic ICU patients, with the SMS showing the best performance overall in our cohort. Our results suggest that models developed from the co-analysis of multiple cohorts are more generalizable. Further work is needed to identify expression-based biomarkers of response to specific therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The data missing from patient profiles in intensive care units (ICUs) are substantial and unavoidable. However, this incompleteness is not always random or because of imperfections in the data collection process., Objective: This study aimed to investigate the potential hidden information in data missing from electronic health records (EHRs) in an ICU and examine whether the presence or missingness of a variable itself can convey information about the patient health status., Methods: Daily retrieval of laboratory test (LT) measurements from the Medical Information Mart for Intensive Care III database was set as our reference for defining complete patient profiles. Missingness indicators were introduced as a way of representing presence or absence of the LTs in a patient profile. Thereafter, various feature selection methods (filter and embedded feature selection methods) were used to examine the predictive power of missingness indicators. Finally, a set of well-known prediction models (logistic regression [LR], decision tree, and random forest) were used to evaluate whether the absence status itself of a variable recording can provide predictive power. We also examined the utility of missingness indicators in improving predictive performance when used with observed laboratory measurements as model input. The outcome of interest was in-hospital mortality and mortality at 30 days after ICU discharge., Results: Regardless of mortality type or ICU day, more than 40% of the predictors selected by feature selection methods were missingness indicators. Notably, employing missingness indicators as the only predictors achieved reasonable mortality prediction on all days and for all mortality types (for instance, in 30-day mortality prediction with LR, we achieved area under the curve of the receiver operating characteristic [AUROC] of 0.6836±0.012). Including indicators with observed measurements in the prediction models also improved the AUROC; the maximum improvement was 0.0426. Indicators also improved the AUROC for Simplified Acute Physiology Score II model-a well-known ICU severity of illness score-confirming the additive information of the indicators (AUROC of 0.8045±0.0109 for 30-day mortality prediction for LR)., Conclusions: Our study demonstrated that the presence or absence of LT measurements is informative and can be considered a potential predictor of in-hospital and 30-day mortality. The comparative analysis of prediction models also showed statistically significant prediction improvement when indicators were included. Moreover, missing data might reflect the opinions of examining clinicians. Therefore, the absence of measurements can be informative in ICUs and has predictive power beyond the measured data themselves. This initial case study shows promise for more in-depth analysis of missing data and its informativeness in ICUs. Future studies are needed to generalize these results., (©Anis Sharafoddini, Joel A Dubin, David M Maslove, Joon Lee. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 08.01.2019.)