Proteomic Evolution from Acute to Post-COVID-19 Conditions.

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Effects of Losartan on Patients Hospitalized for Acute COVID-19: A Randomized Controlled Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19. METHODS: Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25-100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs). RESULTS: The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P = .01; hypotension: 30.4% vs 15.3%, respectively, P < .001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval, .47-2.64]; P = .81), nor did organ dysfunction or secondary outcomes. CONCLUSIONS: Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19. CLINICAL TRIALS REGISTRATION: NCT04606563.

Association of delayed adequate antimicrobial treatment and organ dysfunction in pediatric bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) are associated with significant mortality and morbidity, including multiple organ dysfunction. We explored if delayed adequate antimicrobial treatment for children with BSIs is associated with change in organ dysfunction as measured by PELOD-2 scores. METHODS: We conducted a multicenter, retrospective cohort study of critically ill children <18 years old with BSIs. The primary outcome was change in PELOD-2 score between days 1 (index blood culture) and 5. The exposure variable was delayed administration of adequate antimicrobial therapy by ≥3 h from blood culture collection. We compared PELOD-2 score changes between those who received early and delayed treatment. RESULTS: Among 202 children, the median (interquartile range) time to adequate antimicrobial therapy was 7 (0.8-20.1) hours; 124 (61%) received delayed antimicrobial therapy. Patients who received early and delayed treatment had similar baseline characteristics. There was no significant difference in PELOD-2 score changes from days 1 and 5 between groups (PELOD-2 score difference -0.07, 95% CI -0.92 to 0.79, p = 0.88). CONCLUSIONS: We did not find an association between delayed adequate antimicrobial therapy and PELOD-2 score changes between days 1 and 5 from detection of BSI. PELOD-2 score was not sensitive for clinical effects of delayed antimicrobial treatment. IMPACT: In critically ill children with bloodstream infections, there was no significant change in organ dysfunction as measured by PELOD-2 scores between patients who received adequate antimicrobial therapy within 3 h of their initial positive blood culture and those who started after 3 h. Higher PELOD-2 scores on day 1 were associated with larger differences in PELOD-2 scores between days 1 and 5 from index positive blood cultures. Further study is required to determine if PELOD-2 or alternative measures of organ dysfunction could be used as primary outcome measures in trials of antimicrobial interventions in pediatric critical care research.

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

BACKGROUND: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. METHODS: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. RESULTS: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. INTERPRETATION: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms. CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Do Thresholds for Invasive Ventilation in Hypoxemic Respiratory Failure Exist? A Cohort Study.

Rationale: Invasive ventilation is a significant event for patients with respiratory failure. Physiologic thresholds standardize the use of invasive ventilation in clinical trials, but it is unknown whether thresholds prompt invasive ventilation in clinical practice. Objectives: To measure, in patients with hypoxemic respiratory failure, the probability of invasive ventilation within 3 hours after meeting physiologic thresholds. Methods: We studied patients admitted to intensive care receiving FiO2 of 0.4 or more via nonrebreather mask, noninvasive positive pressure ventilation, or high-flow nasal cannula, using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019) and the Amsterdam University Medical Centers Database (AmsterdamUMCdb) (2003-2016). We evaluated 17 thresholds, including the ratio of arterial to inspired oxygen, the ratio of saturation to inspired oxygen ratio, composite scores, and criteria from randomized trials. We report the probability of invasive ventilation within 3 hours of meeting each threshold and its association with covariates using odds ratios (ORs) and 95% credible intervals (CrIs). Measurements and Main Results: We studied 4,726 patients (3,365 from MIMIC, 1,361 from AmsterdamUMCdb). Invasive ventilation occurred in 28% (1,320). In MIMIC, the highest probability of invasive ventilation within 3 hours of meeting a threshold was 20%, after meeting prespecified neurologic or respiratory criteria while on vasopressors, and 19%, after a ratio of arterial to inspired oxygen of <80 mm Hg. In AmsterdamUMCdb, the highest probability was 34%, after vasopressor initiation, and 25%, after a ratio of saturation to inspired oxygen of <90. The probability after meeting the threshold from randomized trials was 9% (MIMIC) and 13% (AmsterdamUMCdb). In MIMIC, a race/ethnicity of Black (OR, 0.75; 95% CrI, 0.57-0.96) or Asian (OR, 0.6; 95% CrI, 0.35-0.95) compared with White was associated with decreased probability of invasive ventilation after meeting a threshold. Conclusions: The probability of invasive ventilation within 3 hours of meeting physiologic thresholds was low and associated with patient race/ethnicity.

Trends in characteristics, interventions, and outcomes of hospitalized patients with COVID-19 in Canada: a multicentre prospective cohort study.

PURPOSE: Our objective was to investigate the temporal trends in baseline characteristics, interventions, and clinical outcomes in patients hospitalized with COVID-19 in Canada over five pandemic waves. METHODS: We conducted a multicentre prospective cohort study enrolling adults and children admitted with COVID-19 from 47 Canadian hospitals. We compared characteristics, interventions, and outcomes of patients across five distinct pandemic waves. RESULTS: We enrolled 5,285 patients between 2 January 2020 and 8 February 2022. The mean (standard deviation) age was 62.6 (21.0) yr; 41.2% (n = 2,176) were female, and 48% (n = 2,539) required admission to an intensive care unit (ICU), of whom 60.3% (n = 1,530) underwent invasive mechanical ventilation. The proportion of vaccinated patients increased over time. The proportion of vaccinated hospitalized patients progressing to require ICU admission fell over pandemic waves while the proportion of unvaccinated hospitalized patients progressing to require ICU admission did not. Patients were most commonly treated with corticosteroids (48.7%; n = 2,575); use of corticosteroids and other evidence-based treatments increased over time. Hospital mortality was 22.1% (n = 1,166) among all patients, 30.2% (n = 766) among those admitted to an ICU, and 37.9% (n = 580) among those requiring invasive mechanical ventilation. Younger age, absence of chronic cardiac or pulmonary disease, severity of illness at admission, and prior vaccination was associated with a lower mortality; however, pandemic wave itself was not. CONCLUSION: Among patients hospitalized in Canada with COVID-19, several clinical factors including prior vaccination were associated with lower mortality, but pandemic wave was not.

RéSUMé: OBJECTIF: Notre objectif était d'étudier les tendances temporelles des caractéristiques de base, des interventions et des issues cliniques chez la patientèle hospitalisée pour cause de COVID-19 au Canada au cours de cinq vagues de la pandémie. MéTHODE: Nous avons mené une étude de cohorte prospective multicentrique auprès d'adultes et d'enfants admis·es avec la COVID-19 dans 47 hôpitaux canadiens. Nous avons comparé les caractéristiques, les interventions et les issues des patient·es sur cinq vagues pandémiques distinctes. RéSULTATS: Nous avons recruté 5285 patient·es entre le 2 janvier 2020 et le 8 février 2022. L'âge moyen (écart type) était de 62,6 (21,0) ans; 41,2 % (n = 2176) étaient des femmes, et 48 % (n = 2539) ont dû être admis·es à une unité de soins intensifs (USI), dont 60,3 % (n = 1530) ont bénéficié de ventilation mécanique invasive. La proportion de patient·es vacciné·es a augmenté au fil du temps. La proportion de patient·es hospitalisé·es vacciné·es nécessitant une admission aux soins intensifs a diminué au cours des vagues pandémiques, tandis que la proportion de patient·es hospitalisé·es non vacciné·es nécessitant une admission aux soins intensifs n'a pas diminué. Les patient·es étaient le plus souvent traité·es par corticostéroïdes (48,7 %; n = 2575); l'utilisation de corticostéroïdes et d'autres traitements fondés sur des données probantes a augmenté au fil du temps. La mortalité hospitalière était de 22,1 % (n = 1166) parmi l'ensemble des patient·es, 30,2 % (n = 766) chez les personnes admises à l'unité de soins intensifs, et 37,9 % (n = 580) parmi les personnes nécessitant une ventilation mécanique invasive. Le jeune âge, l'absence de maladie cardiaque ou pulmonaire chronique, la gravité de la maladie à l'admission et la vaccination antérieure étaient associés à une mortalité plus faible; cependant, la vague pandémique elle-même ne l'était pas. CONCLUSION: Parmi les personnes hospitalisées au Canada en raison de la COVID-19, plusieurs facteurs cliniques, y compris la vaccination antérieure, étaient associés à une mortalité plus faible, mais pas la vague pandémique.

Using multi-level regression to determine associations and estimate causes and effects in clinical anesthesia due to patient, practitioner and hospital or health system practice variability.

In this research methods tutorial of clinical anesthesia, we will explore techniques to estimate the influence of a myriad of factors on patient outcomes. Big data that contain information on patients, treated by individual anesthesiologists and surgical teams, at different hospitals, have an inherent multi-level data structure (Fig. 1). While researchers often attempt to determine the association between patient factors and outcomes, that does not provide clinicians with the whole story. Patient care is clustered together according to clinicians and hospitals where they receive treatment. Therefore, multi-level regression models are needed to validly estimate the influence of each factor at each level. In addition, we will explore how to estimate the influence that variability-for example, one anesthesiologist deciding to do one thing, while another takes a different approach-has on outcomes for patients, using the intra-class correlation coefficient for continuous outcomes and the median odds ratio for binary outcomes. From this tutorial, you should acquire a clearer understanding of how to perform and interpret multi-level regression modeling and estimate the influence of variable clinical practices on patient outcomes in order to answer common but complex clinical questions. Fig. 1 Infographics.

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).

Feasibility of diffusion-tensor and correlated diffusion imaging for studying white-matter microstructural abnormalities: Application in COVID-19.

There has been growing attention on the effect of COVID-19 on white-matter microstructure, especially among those that self-isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single-shell diffusion magnetic resonance imaging (MRI) methods for detecting such effects. In this work, the performances of three single-shell-compatible diffusion MRI modeling methods are compared for detecting the effect of COVID-19, including diffusion-tensor imaging, diffusion-tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self-isolated patients at the study initiation and 3-month follow-up, along with age- and sex-matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single-shell methods to demonstrate COVID-19-related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID-19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID-19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID-19 related white-matter microstructural pathology manifests as a change in tissue diffusivity. Interestingly, different b-values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3-month follow-up, likely due to the limited size of the follow-up cohort. To summarize, correlated diffusion imaging is shown to be a viable single-shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID-19 patients, suggesting the two regions react differently to viral infection.

Safety Outcomes of Direct Discharge Home From ICUs: An Updated Systematic Review and Meta-Analysis (Direct From ICU Sent Home Study).

OBJECTIVE: To evaluate the impact of direct discharge home (DDH) from ICUs compared with ward transfer on safety outcomes of readmissions, emergency department (ED) visits, and mortality. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature from inception until March 28, 2022. STUDY SELECTION: Randomized and nonrandomized studies of DDH patients compared with ward transfer were eligible. DATA EXTRACTION: We screened and extracted studies independently and in duplicate. We assessed risk of bias using the Newcastle-Ottawa Scale for observational studies. A random-effects meta-analysis model and heterogeneity assessment was performed using pooled data (inverse variance) for propensity-matched and unadjusted cohorts. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Of 10,228 citations identified, we included six studies. Of these, three high-quality studies, which enrolled 49,376 patients in propensity-matched cohorts, could be pooled using meta-analysis. For DDH from ICU, compared with ward transfers, there was no difference in the risk of ED visits at 30-day (22.4% vs 22.7%; relative risk [RR], 0.99; 95% CI, 0.95-1.02; p = 0.39; low certainty); hospital readmissions at 30-day (9.8% vs 9.6%; RR, 1.02; 95% CI, 0.91-1.15; p = 0.71; very low-to-low certainty); or 90-day mortality (2.8% vs 2.6%; RR, 1.06; 95% CI, 0.95-1.18; p = 0.29; very low-to-low certainty). There were no important differences in the unmatched cohorts or across subgroup analyses. CONCLUSIONS: Very low-to-low certainty evidence from observational studies suggests that DDH from ICU may have no difference in safety outcomes compared with ward transfer of selected ICU patients. In the future, this research question could be further examined by randomized control trials to provide higher certainty data.

MRI Assessment of Cerebral Blood Flow in Nonhospitalized Adults Who Self-Isolated Due to COVID-19.

BACKGROUND: Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe. PURPOSE: To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19. STUDY TYPE: Prospective observational. POPULATION: A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). FIELD STRENGTH AND SEQUENCES: A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences. ASSESSMENT: Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group. STATISTICAL TESTS: Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05. RESULTS: Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue. DATA CONCLUSION: These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts.

BACKGROUND: The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. METHODS: This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008-2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003-2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF < 110, < 98, and < 88 on 28-day mortality. MIMIC-IV was used for the primary analysis and AmsterdamUMCdb for the secondary analysis. We obtained posterior means and 95% credible intervals (CrI) with nonparametric Bayesian G-computation. RESULTS: We studied 3,357 patients in the primary analysis. For invasive ventilation initiation thresholds SF < 110, SF < 98, and SF < 88, the predicted 28-day probabilities of invasive ventilation were 72%, 47%, and 19%. Predicted 28-day mortality was lowest with threshold SF < 110 (22.2%, CrI 19.2 to 25.0), compared to SF < 98 (absolute risk increase 1.6%, CrI 0.6 to 2.6) or SF < 88 (absolute risk increase 3.5%, CrI 1.4 to 5.4). In the secondary analysis (1,279 patients), the predicted 28-day probability of invasive ventilation was 50% for initiation threshold SF < 110, 28% for SF < 98, and 19% for SF < 88. In contrast with the primary analysis, predicted mortality was highest with threshold SF < 110 (14.6%, CrI 7.7 to 22.3), compared to SF < 98 (absolute risk decrease 0.5%, CrI 0.0 to 0.9) or SF < 88 (absolute risk decrease 1.9%, CrI 0.9 to 2.8). CONCLUSION: Initiating invasive ventilation at lower hypoxemia severity will increase the rate of invasive ventilation, but this can either increase or decrease the expected mortality, with the direction of effect likely depending on baseline mortality risk and clinical context.

Longitudinal Plasma Proteomics Analysis Reveals Novel Candidate Biomarkers in Acute COVID-19.

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Outcomes After Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis.

OBJECTIVES: To compare health service use and clinical outcomes for patients with and without direct discharge to home (DDH) from ICUs in Ontario. DESIGN: Population-based, observational, cohort study using propensity scoring to match patients who were DDH to those not DDH and a preference-based instrumental variable (IV) analysis using ICU-level DDH rate as the IV. SETTING: ICUs in Ontario. PATIENTS: Patients discharged home from a hospitalization either directly or within 48 hours of care in an ICU between April 1, 2015, and March 31, 2017. INTERVENTION: DDH from ICU. MEASUREMENTS AND MAIN RESULTS: Among 76,737 patients in our cohort, 46,859 (61%) were DDH from the ICU. In the propensity matched cohort, the odds for our primary outcome of hospital readmission or emergency department (ED) visit within 30 days were not significantly different for patients DDH (odds ratio [OR], 1.00; 95% CI, 0.96-1.04), and there was no difference in mortality at 90 days for patients DDH (OR, 1.08; 95% CI, 0.97-1.21). The effect on hospital readmission or ED visits was similar in the subgroup of patients discharged from level 2 (OR, 0.98; 95% CI, 0.92-1.04) and level 3 ICUs (OR, 1.02; 95% CI, 0.96-1.09) and in the subgroups with cardiac conditions (OR, 1.03; 95% CI, 0.96-1.12) and noncardiac conditions (OR, 0.98; 95% CI, 0.94-1.03). Similar results were obtained in the IV analysis (coefficient for hospital readmission or ED visit within 30 d = -0.03 ± 0.03 ( se ); p = 0.3). CONCLUSIONS: There was no difference in outcomes for patients DDH compared with ward transfer prior to discharge when two approaches were used to minimize confounding within a large health systemwide observational cohort. We did not evaluate how patients are selected for DDH. Our results suggest that with careful patient selection, this practice might be feasible for routine implementation to ensure efficient and safe use of limited healthcare resources.

Prognostic Factors Associated With Development of Venous Thromboembolism in Critically Ill Patients-A Systematic Review and Meta-Analysis.

OBJECTIVE: To identify prognostic factors for the development of venous thromboembolism in the ICU. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to March 1, 2021. STUDY SELECTION: We included English-language studies describing prognostic factors associated with the development of venous thromboembolism among critically ill patients. DATA EXTRACTION: Two authors performed data extraction and risk-of-bias assessment. We pooled adjusted odds ratios and adjusted hazard ratios for prognostic factors using random-effects model. We assessed risk of bias using the Quality in Prognosis Studies tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. DATA SYNTHESIS: We included 39 observational cohort studies involving 729,477 patients. Patient factors with high or moderate certainty of association with increased odds of venous thromboembolism include older age (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29 per 10 yr), obesity (adjusted odds ratio, 1.25; 95% CI, 1.18-1.32), active malignancy (adjusted odds ratio, 1.70; 95% CI, 1.18-2.44), history of venous thromboembolism (adjusted odds ratio, 4.77; 95% CI, 3.42-6.65), and history of recent surgery (adjusted odds ratio, 1.77; 95% CI, 1.26-2.47). ICU-specific factors with high or moderate certainty of association with increased risk of venous thromboembolism include sepsis (adjusted odds ratio, 1.41; 95% CI, 1.12-1.78), lack of pharmacologic venous thromboembolism prophylaxis (adjusted odds ratio, 1.80; 95% CI, 1.14-2.84), central venous catheter (adjusted odds ratio, 2.93; 95% CI, 1.98-4.34), invasive mechanical ventilation (adjusted odds ratio, 1.74; 95% CI, 1.36-2.24), and use of vasoactive medication (adjusted odds ratio, 1.86; 95% CI, 1.23-2.81). CONCLUSIONS: This meta-analysis provides quantitative summaries of the association between patient-specific and ICU-related prognostic factors and the risk of venous thromboembolism in the ICU. These findings provide the foundation for the development of a venous thromboembolism risk stratification tool for critically ill patients.

Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19.

OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study.

BACKGROUND: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). METHODS: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. RESULTS: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). CONCLUSIONS: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.

Quantitative Assessment of Viral Dispersion Associated with Respiratory Support Devices in a Simulated Critical Care Environment.

Rationale: Patients with severe coronavirus disease (COVID-19) require supplemental oxygen and ventilatory support. It is unclear whether some respiratory support devices may increase the dispersion of infectious bioaerosols and thereby place healthcare workers at increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Objectives: To quantitatively compare viral dispersion from invasive and noninvasive respiratory support modalities.Methods: This study used a simulated ICU room with a breathing-patient simulator exhaling nebulized bacteriophages from the lower respiratory tract with various respiratory support modalities: invasive ventilation (through an endotracheal tube with an inflated cuff connected to a mechanical ventilator), helmet ventilation with a positive end-expiratory pressure (PEEP) valve, noninvasive bilevel positive-pressure ventilation, nonrebreather face masks, high-flow nasal oxygen (HFNO), and nasal prongs.Measurements and Main Results: Invasive ventilation and helmet ventilation with a PEEP valve were associated with the lowest bacteriophage concentrations in the air, and HFNO and nasal prongs were associated with the highest concentrations. At the intubating position, bacteriophage concentrations associated with HFNO (2.66 × 104 plaque-forming units [PFU]/L of air sampled), nasal prongs (1.60 × 104 PFU/L of air sampled), nonrebreather face masks (7.87 × 102 PFU/L of air sampled), and bilevel positive airway pressure (1.91 × 102 PFU/L of air sampled) were significantly higher than those associated with invasive ventilation (P < 0.05 for each). The difference between bacteriophage concentrations associated with helmet ventilation with a PEEP valve (4.29 × 10-1 PFU/L of air sampled) and bacteriophage concentrations associated with invasive ventilation was not statistically significant.Conclusions: These findings highlight the potential differential risk of dispersing virus among respiratory support devices and the importance of appropriate infection prevention and control practices and personal protective equipment for healthcare workers when caring for patients with transmissible respiratory viral infections such as SARS-CoV-2.

Impact of restricted visitation policies during COVID-19 on critically ill adults, their families, critical care clinicians, and decision-makers: a qualitative interview study.

PURPOSE: During the first wave of the COVID-19 pandemic, restricted visitation policies were enacted at acute care facilities to reduce the spread of COVID-19 and conserve personal protective equipment. In this study, we aimed to describe the impact of restricted visitation policies on critically ill patients, families, critical care clinicians, and decision-makers; highlight the challenges faced in translating these policies into practice; and delineate strategies to mitigate their effects. METHOD: A qualitative description design was used. We conducted semistructured interviews with critically ill adult patients and their family members, critical care clinicians, and decision-makers (i.e., policy makers or enforcers) affected by restricted visitation policies. We transcribed semistructured interviews verbatim and analyzed the transcripts using inductive thematic analysis. RESULTS: Three patients, eight family members, 30 clinicians (13 physicians, 17 nurses from 23 Canadian intensive care units [ICUs]), and three decision-makers participated in interviews. Thematic analysis was used to identify five themes: 1) acceptance of restricted visitation (e.g., accepting with concerns); 2) impact of restricted visitation (e.g., ethical challenges, moral distress, patients dying alone, intensified workload); 3) trust in the healthcare system during the pandemic (e.g., mistrust of clinical team); 4) modes of communication (e.g., communication using virtual platforms); and 5) impact of policy implementation on clinical practice (e.g., frequent changes and inconsistent implementation). CONCLUSIONS: Restricted visitation policies across ICUs during the COVID-19 pandemic negatively affected critically ill patients and their families, critical care clinicians, and decision-makers.

RéSUMé: OBJECTIF: Au cours de la première vague de la pandémie de COVID-19, des politiques de visite restreintes ont été adoptées dans les établissements de soins aigus afin de réduire la propagation de la COVID-19 et d'économiser les équipements de protection individuelle. Dans cette étude, nous avons cherché à décrire l'impact des politiques de visite restreintes sur les patients gravement malades, les familles, les intensivistes et les décideurs, ainsi qu'à souligner les difficultés rencontrées dans la mise en pratique de ces politiques et à définir des stratégies pour en atténuer les effets. MéTHODE: Une méthodologie de description qualitative a été utilisée. Nous avons mené des entretiens semi-structurés avec des patients adultes gravement malades et les membres de leur famille, les intensivistes et les décideurs (c.-à-d. les stratèges ou les responsables de l'application de la loi) touchés par les politiques de visite restreintes. Nous avons transcrit textuellement les entretiens semi-structurés et analysé les transcriptions à l'aide d'une analyse thématique inductive. RéSULTATS: Trois patients, huit membres de leur famille, 30 cliniciens (13 médecins, 17 infirmières de 23 unités de soins intensifs canadiennes) et trois décideurs ont participé à ces entrevues. L'analyse thématique a été utilisée pour identifier cinq thèmes : 1) l'acceptation des visites restreintes (p. ex., accepter avec des préoccupations); 2) l'impact des visites restreintes (p. ex., défis éthiques, détresse morale, patients mourant seuls, charge de travail accrue); 3) la confiance dans le système de santé pendant la pandémie (p. ex., méfiance à l'égard de l'équipe clinique); 4) les modes de communication (p. ex., communication à l'aide de plateformes virtuelles); et 5) l'incidence de la mise en œuvre des politiques sur la pratique clinique (p. ex., changements fréquents et mise en œuvre incohérente). CONCLUSION: Les politiques de visite restreintes dans les unités de soins intensifs pendant la pandémie de COVID-19 ont eu un impact négatif sur les patients gravement malades et leurs familles, les intensivistes et les décideurs.