Impact of sample processing delays on plasma markers of inflammation, chemotaxis, cell death, and blood coagulation.

BACKGROUND: Biosampling studies in critically ill patients traditionally involve bedside collection of samples followed by local processing (ie. centrifugation, aliquotting, and freezing) and storage. However, community hospitals, which care for the majority of Canadian patients, often lack the infrastructure for local processing and storage of specimens. A potential solution is a "simplified" biosampling protocol whereby blood samples are collected at the bedside and then shipped to a central site for processing and storage. One potential limitation of this approach is that delayed processing may alter sample characteristics. OBJECTIVE: To determine whether delays in blood sample processing affect the stability of cytokines (IL-6, TNF, IL-10, IFN-γ), chemokines (IL-8, IP-10, MCP-1, MCP-4, MIP-1α, MIP-1ß), cell-free DNA (cfDNA) (released by dying cells), and blood clotting potential in human blood samples. METHODS: Venous blood was collected into EDTA and citrate sample tubes and stored at room temperature (RT) or 4°C for progressive intervals up to 72 hours, prior to processing. Plasma cytokines and chemokines were quantified using single or multiplex immunoassays. cfDNA was measured using Picogreen DNA Quantification. Blood clotting potential was measured using a thrombin generation assay. RESULTS: Blood samples were collected from 9 intensive care unit (ICU) patients and 7 healthy volunteers. Admission diagnoses for the ICU patients included sepsis, trauma, ruptured abdominal aortic aneurysm, intracranial hemorrhage, gastrointestinal bleed, and hyperkalemia. After pre-processing delays of up to 72 hours at RT or 4°C, no significant changes were observed in plasma cytokines, chemokines, cfDNA, or thrombin formation. CONCLUSIONS: Delayed sample processing for up to 72 hours at either RT or 4°C did not significantly affect cytokines, chemokines, cfDNA, or blood clotting potential in plasma samples from healthy volunteers and ICU patients. A "simplified" biosampling protocol is a feasible solution for conducting biosampling research at hospitals without local processing capacity.

Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

Barriers to participation in biosampling-based translational research: A cross-sectional survey of Canadian critical care researchers.

BACKGROUND AND OBJECTIVE: Collection of biosamples for translational research studies is vital for understanding biological pathways, discovering disease-related biomarkers, and identifying novel therapeutic targets. However, a lack of infrastructure for sample procurement, processing, storage, and shipping may hinder the ability of clinical research units to effectively engage in translational research. The purpose of this study was to identify the barriers to biosampling-based translational research in the critical care setting in Canada. METHODS: We administered an online survey to members of the Canadian Critical Care Trials Group (CCCTG), the Canadian Critical Care Translational Biology Group (CCCTBG), and the Canadian Critical Care Research Coordinators Group (CCCRCG). The survey focused on participants' personal experience of biosampling research, research infrastructure, motivating factors, and perceived barriers. RESULTS: We received 59 responses from 31 sites, including 6 community intensive care unit (ICU) sites. The overall response rate was 11.3%. The majority of respondents were research coordinators (44%), followed by clinician-investigators (33.8%), graduate students (10.2%), and PhD-investigators (8.5%). Although most (63.8%) respondents reported an interest in participating in translational research, they also reported that their ICUs were currently contributing to a third of the number of translational studies compared to clinical studies. For respondents with experience in participating in translational research studies, the most common barriers were lack of funding, lack of time, and insufficient research staff. For respondents without previous experience, the perceived facilitators were more interest from their research group, improved training/mentorship, increased funding, and better access to laboratory equipment. CONCLUSIONS: Our survey found that the majority of participants were interested in and recognize the value of participating in biosampling-based translational research but lacked funding, time, and research personnel trained in biosampling protocols. Our survey also identified factors that might encourage participation at new sites. Addressing these barriers will be a key step towards increasing translational research capacity across Canada.

COVID-19 Immunologic Antiviral Therapy With Omalizumab (CIAO)-a Randomized Controlled Clinical Trial.

Background: Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties. Objective: We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Methods: This was a phase II randomized, double blind, placebo-controlled trial comparing omalizumab with placebo (in addition to standard of care) in hospitalized patients with COVID-19. The primary endpoint was the composite of mechanical ventilation and/or death at day 14. Secondary endpoints included all-cause mortality at day 28, time to clinical improvement, and duration of hospitalization. Results: Of 41 patients recruited, 40 were randomized (20 received the study drug and 20 placebo). The median age of the patients was 74 years and 55.0% were male. Omalizumab was associated with a 92.6% posterior probability of a reduction in mechanical ventilation and death on day 14 with an adjusted odds ratio of 0.11 (95% credible interval 0.002-2.05). Omalizumab was also associated with a 75.9% posterior probability of reduced all-cause mortality on day 28 with an adjusted odds ratio of 0.49 (95% credible interval, 0.06-3.90). No statistically significant differences were found for the time to clinical improvement and duration of hospitalization. Numerically fewer adverse events were reported in the omalizumab group and there were no drug-related serious adverse events. Conclusions: These results suggest that omalizumab could prove protective against death and mechanical ventilation in hospitalized patients with COVID-19. This study could also support the development of a phase III trial program investigating the antiviral and anti-inflammatory effect of omalizumab for severe respiratory viral illnesses requiring hospital admission. ClinicalTrials.gov ID: NCT04720612.

Canadian intensive care unit nurses' responses to moral distress during the COVID-19 pandemic, and their recommendations for mitigative interventions.

AIMS: To describe intensive care unit nurses' experiences of moral distress during the COVID-19 pandemic, and their recommendations for mitigative interventions. DESIGN: Interpretive description. METHODS: Data were collected with a purposeful sample of 40 Canadian intensive care unit nurses between May and September 2021. Nurses completed a demographic questionnaire, the Measure of Moral Distress-Healthcare Professionals survey and in-depth interviews. Quantitative data were analysed using descriptive statistics. Qualitative data were categorized and synthesized using reflexive thematic analysis and rapid qualitative analysis. RESULTS: Half of the nurses in this sample reported moderate levels of moral distress. In response to moral distress, nurses experienced immediate and long-term effects across multiple health domains. To cope, nurses discussed varied reactions, including action, avoidance and acquiescence. Nurses provided recommendations for interventions across multiple organizations to mitigate moral distress and negative health outcomes. CONCLUSION: Nurses reported that moral distress drove negative health outcomes and attrition in response to moral events in practice. To change these conditions of moral distress, nurses require organizational investments in interventions and cultures that prioritize the inclusion of nursing perspectives and voices. IMPLICATIONS FOR THE PROFESSION: Nurses engage in a variety of responses to cope with moral distress. They possess valuable insights into the practice issues central to moral distress that have significant implications for all members of the healthcare teams, patients and systems. It is essential that nurses' voices be included in the development of future interventions central to the responses to moral distress. REPORTING METHOD: This study adheres to COREQ guidelines. IMPACT: What Problem did the Study Address? Given the known structural, systemic and environmental factors that contribute to intensive care unit nurses' experiences of moral distress, and ultimately burnout and attrition, it was important to learn about their experiences of moral distress and their recommendations for organizational mitigative interventions. Documentation of these experiences and recommendations took on a greater urgency during the context of a global health emergency, the COVID-19 pandemic, where such contextual influences on moral distress were less understood. What Were the Main Findings? Over half of the nurses reported a moderate level of moral distress. Nurses who were considering leaving nursing practice reported higher moral distress scores than those who were not considering leaving. In response to moral distress, nurses experienced a variety of outcomes across several health domains. To cope with moral distress, nurses engaged in patterns of action, avoidance and acquiescence. To change the conditions of moral distress, nurses desire organizational interventions, practices and culture changes situated in the amplification of their voices. Where and on Whom Will the Research Have an Impact on? These findings will be of interest to: (1) researchers developing and evaluating interventions that address the complex phenomenon of moral distress, (2) leaders and administrators in hospitals, and relevant healthcare and nursing organizations, and (3) nurses interested in leveraging evidence-informed recommendations to advocate for interventions to address moral distress. What Does this Paper Contribute to the Wider Global Community? This paper advances the body of scientific work on nurses' experiences of moral distress, capturing this phenomenon within the unique context of a global health emergency. Nurses' levels of moral distress using Measure of Moral Distress-Healthcare Professional survey were reported, serving as a comparator for future studies seeking to measure and evaluate intensive care unit nurses' levels of moral distress. Nurses' recommendations for mitigative interventions for moral distress have been reported, which can help inform future interventional studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

The impact of COVID-19 workload on psychological distress amongst Canadian intensive care unit healthcare workers during the 1st wave of the COVID-19 pandemic: A longitudinal cohort study.

Intensive care unit healthcare workers (ICU HCW) are at risk of mental health disorders during emerging disease outbreaks. Numerous cross-sectional studies have reported psychological distress, anxiety, and depression amongst ICU HCW during the COVID-19 pandemic. However, few studies have followed HCW longitudinally, and none of these have examined the association between COVID-19 workload and mental health. We conducted a longitudinal cohort study of 309 Canadian ICU HCW from April 2020 to August 2020, during the 1st wave of the COVID-19 pandemic. Psychological distress was assessed using the General Health Questionnaire 12-item scale (GHQ-12) at 3 timepoints: during the acceleration phase of the 1st wave (T1), the deceleration phase of the 1st wave (T2), and after the 1st wave had passed (T3). Clinically relevant psychological distress, defined as a GHQ-12 score ≥ 3, was identified in 64.7% of participants at T1, 41.0% at T2, and 34.6% at T3. Psychological distress was not associated with COVID-19 workload at T1. At T2, psychological distress was associated with the number of COVID-19 patients in the ICU (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.00, 1.13) while at T3, when COVID-19 patient numbers were low, it was associated with the number of weekly hospital shifts with COVID-19 exposure (OR: 1.33, 95% CI: 1.09, 1.64). When analyzed longitudinally in a mixed effects model, pandemic timepoint was a stronger predictor of psychological distress (OR: 0.24, 95% CI: 0.15, 0.40 for T2 and OR: 0.16, 95% CI: 0.09, 0.27 for T3) than COVID-19 workload. Participants who showed persistent psychological distress at T3 were compared with those who showed recovery at T3. Persistent psychological distress was associated with a higher number of weekly shifts with COVID-19 exposure (OR: 1.97, 95% CI:1.33, 3.09) but not with a higher number of COVID-19 patients in the ICU (OR: 0.86, 95% CI: 0.76, 0.95). In summary, clinically relevant psychological distress was observed in a majority of ICU HCW during the acceleration phase of the 1st wave of the COVID-19 pandemic but decreased rapidly as the 1st wave progressed. Persistent psychological distress was associated with working more weekly shifts with COVID-19 exposure but not with higher numbers of COVID-19 patients in the ICU. In future emerging disease outbreaks, minimizing shifts with direct disease exposure may help alleviate symptoms for individuals with persistent psychological distress.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Frequency of screening and SBT Technique Trial-North American Weaning Collaboration (FAST-NAWC): an update to the protocol and statistical analysis plan.

BACKGROUND: This update summarizes key changes made to the protocol for the Frequency of Screening and Spontaneous Breathing Trial (SBT) Technique Trial-North American Weaning Collaborative (FAST-NAWC) trial since the publication of the original protocol. This multicenter, factorial design randomized controlled trial with concealed allocation, will compare the effect of both screening frequency (once vs. at least twice daily) to identify candidates to undergo a SBT and SBT technique [pressure support + positive end-expiratory pressure vs. T-piece] on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American intensive care units. METHODS/DESIGN: Protocols for the pilot, factorial design trial and the full trial were previously published in J Clin Trials ( https://doi.org/10.4172/2167-0870.1000284 ) and Trials (https://doi: 10.1186/s13063-019-3641-8). As planned, participants enrolled in the FAST pilot trial will be included in the report of the full FAST-NAWC trial. In response to the onset of the coronavirus disease of 2019 (COVID-19) pandemic when approximately two thirds of enrollment was complete, we revised the protocol and consent form to include critically ill invasively ventilated patients with COVID-19. We also refined the statistical analysis plan (SAP) to reflect inclusion and reporting of participants with and without COVID-19. This update summarizes the changes made and their rationale and provides a refined SAP for the FAST-NAWC trial. These changes have been finalized before completion of trial follow-up and the commencement of data analysis. TRIAL REGISTRATION: Clinical Trials.gov NCT02399267.

Time required to initiate a clinical trial in Canada at the onset of the COVID-19 pandemic: an observational research-in-motion study.

BACKGROUND: Randomized controlled trials (RCTs) provide essential evidence to inform practice, but the many necessary steps result in lengthy times to initiation, which is problematic in the case of rapidly emerging infections such as COVID-19. This study aimed to describe the start-up timelines for the Canadian Treatments for COVID-19 (CATCO) RCT. METHODS: We surveyed hospitals participating in CATCO and ethics submission sites using a structured data abstraction form. We measured durations from protocol receipt to site activation and to first patient enrolment, as well as durations of administrative processes, including research ethics board (REB) approval, contract execution and lead times between approvals to site activation. RESULTS: All 48 hospitals (26 academic, 22 community) and 4 ethics submission sites responded. The median time from protocol receipt to trial initiation was 111 days (interquartile range [IQR] 39-189 d, range 15-412 d). The median time between protocol receipt and REB submission was 41 days (IQR 10-56 d, range 4-195 d), from REB submission to approval, 4.5 days (IQR 1-12 d, range 0-169 d), from REB approval to site activation, 35 days (IQR 22-103 d, range 0-169 d), from protocol receipt to contract submission, 42 days (IQR 20-51 d, range 4-237 d), from contract submission to full contract execution, 24 days (IQR 15-58 d, range 5-164 d) and from contract execution to site activation, 10 days (IQR 6-27 d, range 0-216 d). Processes took longer in community hospitals than in academic hospitals. INTERPRETATION: The time required to initiate RCTs in Canada was lengthy and varied among sites. Adoption of template clinical trial agreements, greater harmonization or central coordination of ethics submissions, and long-term funding of platform trials that engage academic and community hospitals are potential solutions to improve trial start-up efficiency.

Critical Care Cycling to Improve Lower Extremity Strength (CYCLE): protocol for an international, multicentre randomised clinical trial of early in-bed cycling for mechanically ventilated patients.

INTRODUCTION: In-bed leg cycling with critically ill patients is a promising intervention aimed at minimising immobility, thus improving physical function following intensive care unit (ICU) discharge. We previously completed a pilot randomised controlled trial (RCT) which supported the feasibility of a large RCT. In this report, we describe the protocol for an international, multicentre RCT to determine the effectiveness of early in-bed cycling versus routine physiotherapy (PT) in critically ill, mechanically ventilated adults. METHODS AND ANALYSIS: We report a parallel group RCT of 360 patients in 17 medical-surgical ICUs and three countries. We include adults (≥18 years old), who could ambulate independently before their critical illness (with or without a gait aid), ≤4 days of invasive mechanical ventilation and ≤7 days ICU length of stay, and an expected additional 2-day ICU stay, and who do not fulfil any of the exclusion criteria. After obtaining informed consent, patients are randomised using a web-based, centralised system to either 30 min of in-bed cycling in addition to routine PT, 5 days per week, up to 28 days maximum, or routine PT alone. The primary outcome is the Physical Function ICU Test-scored (PFIT-s) at 3 days post-ICU discharge measured by assessors blinded to treatment allocation. Participants, ICU clinicians and research coordinators are not blinded to group assignment. Our sample size estimate was based on the identification of a 1-point mean difference in PFIT-s between groups. ETHICS AND DISSEMINATION: Critical Care Cycling to improve Lower Extremity (CYCLE) is approved by the Research Ethics Boards of all participating centres and Clinical Trials Ontario (Project 1345). We will disseminate trial results through publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot).

Academic and Community ICUs Participating in a Critical Care Randomized Trial: A Comparison of Patient Characteristics and Trial Metrics.

Clinical research in Canada is conducted primarily in "academic" hospitals, whereas most clinical care is provided in "community" hospitals. The objective of this nested observational study was to compare patient characteristics, outcomes, process-of-care variables, and trial metrics for patients enrolled in a large randomized controlled trial who were admitted to academic and community hospitals in Canada. DESIGN: We conducted a preplanned observational study nested within the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT, a randomized controlled trial comparing probiotics to placebo in mechanically ventilated patients) Research Program. SETTING: ICUs. PATIENTS: Mechanically ventilated patients. MEASUREMENTS: We compared patient characteristics, interventions, outcomes, and trial metrics between patients enrolled in PROSPECT from academic and community hospitals. MAIN RESULTS: Participating centers included 34 (82.9%) academic and seven (17.1%) community hospitals, which enrolled 2,203 (86.2%) and 352 (13.8%) patients, respectively. Compared with academic hospitals, patients enrolled in community hospitals were older (mean [sd] 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), had longer ICU stays (median [interquartile range {IQR}], 13 d [8-23 d] vs 11 d [7-8 d]; p = 0.012) and higher mortality (percentage, [95% CI] in the ICU, 30.4% [25.8-35.4%]vs 20.5% [18.9-11.3%]; p = 0.002) and hospital (40.6% [35.6-45.8%] vs 26.1% [24.3-27.9%]; p < 0.001). Trial metrics, including informed consent rate (85.9% vs 76.3%; p = 0.149), mean (sd) monthly enrolment rate (2.1 [1.4] vs 1.1 [0.7]; p = 0.119), and protocol adherence (90.6% vs 91.6%; p = 0.207), were similar between community and academic ICUs. CONCLUSIONS: Community hospitals can conduct high-quality research, with similar trial metrics to academic hospitals. Patient characteristics differed between community and academic hospitals, highlighting the need for broader engagement of community hospitals in clinical research to ensure generalizability of study results.

Cost-effectiveness of remdesivir plus usual care versus usual care alone for hospitalized patients with COVID-19: an economic evaluation as part of the Canadian Treatments for COVID-19 (CATCO) randomized clinical trial.

BACKGROUND: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir. METHODS: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed. RESULTS: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation. INTERPRETATION: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation. STUDY REGISTRATION: ClinicalTrials. gov, no. NCT04330690.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Research interrupted: applying the CONSERVE 2021 Statement to a randomized trial of rehabilitation during critical illness affected by the COVID-19 pandemic.

RATIONALE: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) statement as a framework to report the impact of the pandemic on CYCLE and describe our mitigation approaches. METHODS: On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy) and collect the primary outcome (physical function 3-days post-ICU discharge) and 90-day outcomes. We advised sites to prioritize data for the study's primary outcome. We sought feedback on pandemic barriers related to trial procedures. RESULTS: Our main Methods Centre mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, developing standardized internal tools focused on high-risk points in the protocol for monitoring patient progress, data entry, and validation, and providing guidance to conduct some research activities remotely. For study sites, our strategies included determining how institutional pandemic research policies applied to CYCLE, communicating with the Methods Centre about capacity to continue any part of the research, and developing contingency plans to ensure the protocol was delivered as intended. From 15 active sites (12 Canada, 2 US, 1 Australia), 5 patients were still receiving the study intervention in ICUs, 6 required primary outcomes, and 17 required 90-day assessments. With these mitigation strategies, we attempted 100% of ICU interventions, 83% of primary outcomes, and 100% of 90-day assessments per our protocol. CONCLUSIONS: We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that it also provides a helpful framework for reporting mitigation strategies with the goal of improving research transparency and trial management. TRIAL REGISTRATION: NCT03471247. Registered on March 20, 2018.

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial.

Importance: The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19. Objective: To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19. Design, Setting, and Participants: Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021. Intervention: Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195). Main Outcomes and Measures: The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events. Results: Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, -6.37% [95% CI, -15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, -1.15% [95% CI, -9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group. Conclusions and Relevance: In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT04350723.

Motivating factors, barriers and facilitators of participation in COVID-19 clinical research: A cross-sectional survey of Canadian community intensive care units.

Only a small proportion of COVID-19 patients in Canada have been recruited into clinical research studies. One reason is that few community intensive care units (ICUs) in Canada participate in research. The objective of this study was to examine the motivating factors, barriers and facilitators to research participation amongst Canadian community ICU stakeholders. A cross-sectional online survey was distributed between May and November 2020. The survey focused on 6 domains: participant demographics, ICU characteristics, ICU research infrastructure, motivating factors, perceived barriers, and perceived facilitators. Responses were received from 73 community ICU stakeholders, representing 18 ICUs. 7/18 ICUs had a clinical research program. Participants rated their interest in pandemic research at a mean of 5.2 (Standard Deviation [SD] = 1.9) on a 7-point Likert scale from 'not interested' to 'very interested'. The strongest motivating factor for research participation was the belief that research improves clinical care and outcomes. The most significant facilitators of research involvement were the availability of an experienced research coordinator and dedicated external funding to cover start-up costs, while the most significant barriers to research involvement were a lack of start-up funding for a research coordinator and a lack of ICU research experience. Canadian Community ICU stakeholders are interested in participating in pandemic research but lack basic infrastructure, research personnel, research experience and start-up funding. Evolution of a research support model at community hospitals, where most patients receive acute care, may increase research participation and improve the generalizability of funded research in Canada.

External validation of the 4C mortality score among COVID-19 patients admitted to hospital in Ontario, Canada: a retrospective study.

Risk prediction scores are important tools to support clinical decision-making for patients with coronavirus disease (COVID-19). The objective of this paper was to validate the 4C mortality score, originally developed in the United Kingdom, for a Canadian population, and to examine its performance over time. We conducted an external validation study within a registry of COVID-19 positive hospital admissions in the Kitchener-Waterloo and Hamilton regions of southern Ontario between March 4, 2020 and June 13, 2021. We examined the validity of the 4C score to prognosticate in-hospital mortality using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals calculated via bootstrapping. The study included 959 individuals, of whom 224 (23.4%) died in-hospital. Median age was 72 years and 524 individuals (55%) were male. The AUC of the 4C score was 0.77, 95% confidence interval 0.79-0.87. Overall mortality rates across the pre-defined risk groups were 0% (Low), 8.0% (Intermediate), 27.2% (High), and 54.2% (Very High). Wave 1, 2 and 3 values of the AUC were 0.81 (0.76, 0.86), 0.74 (0.69, 0.80), and 0.76 (0.69, 0.83) respectively. The 4C score is a valid tool to prognosticate mortality from COVID-19 in Canadian hospitals and can be used to prioritize care and resources for patients at greatest risk of death.

Psychosocial distress amongst Canadian intensive care unit healthcare workers during the acceleration phase of the COVID-19 pandemic.

Intensive care unit healthcare workers (ICU HCW) are at risk of mental health issues during emerging disease outbreaks. A study of ICU HCW from France revealed symptoms of anxiety and depression in 50.4% and 30.4% of workers at the peak of the first wave of the pandemic. The level of COVID-19 exposure of these ICU HCW was very high. In Canada, ICU HCW experienced variable exposure to COVID-19 during the first wave of the pandemic, with some hospitals seeing large numbers of patients while others saw few or none. In this study we examined the relationship between COVID-19 exposure and mental health in Canadian ICU HCW. We conducted a cross-sectional cohort study of Canadian ICU HCW in April 2020, during the acceleration phase of the first wave of the pandemic. Psychosocial distress was assessed using the 12-item General Health Questionnaire (GHQ-12). Participants were asked about sources of stress as well as about exposure to COVID-19 patients and availability of personal protective equipment (PPE). Factors associated with clinically-relevant psychosocial distress were identified. Responses were received from 310 Canadian ICU HCW affiliated with more than 30 institutions. Of these, 64.5% scored ≥ 3 points on the GHQ-12 questionnaire, indicating clinically-relevant psychosocial distress. The frequency of psychosocial distress was highest amongst registered nurses (75.7%) and lowest amongst physicians (49.4%). It was also higher amongst females (64.9%) than males (47.6%). Although PPE availability was good (> 80% of participants reported adequate availability), there was significant anxiety with respect to PPE availability, with respect to the risk of being infected with COVID-19, and with respect to the risk of transmitting COVID-19 to others. In multivariable regression analysis, Anxiety with respect to being infected with COVID-19 (OR 1.53, CI 1.31-1.81) was the strongest positive predictor of clinically-relevant psychosocial distress while the Number of shifts with COVID-19 exposure (OR 0.86, CI 0.75-0.95) was the strongest negative predictor. In summary, clinically-relevant psychosocial distress was identified amongst a majority of ICU HCW during the acceleration phase of the first wave of the COVID-19 pandemic, including those with minimal or no exposure to COVID-19. Strategies to support mental health amongst ICU HCW are required across the entire healthcare system.

Incidence and Outcomes of Acute Kidney Injury in Patients Admitted to Hospital With COVID-19: A Retrospective Cohort Study.

BACKGROUND: The incidence of acute kidney injury (AKI) in patients with COVID-19 and its association with mortality and disease severity is understudied in the Canadian population. OBJECTIVE: To determine the incidence of AKI in a cohort of patients with COVID-19 admitted to medicine and intensive care unit (ICU) wards, its association with in-hospital mortality, and disease severity. Our aim was to stratify these outcomes by out-of-hospital AKI and in-hospital AKI. DESIGN: Retrospective cohort study from a registry of patients with COVID-19. SETTING: Three community and 3 academic hospitals. PATIENTS: A total of 815 patients admitted to hospital with COVID-19 between March 4, 2020, and April 23, 2021. MEASUREMENTS: Stage of AKI, ICU admission, mechanical ventilation, and in-hospital mortality. METHODS: We classified AKI by comparing highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We calculated the unadjusted and adjusted odds ratio for the stage of AKI and the outcomes of ICU admission, mechanical ventilation, and in-hospital mortality. RESULTS: Of the 815 patients registered, 439 (53.9%) developed AKI, 253 (57.6%) presented with AKI, and 186 (42.4%) developed AKI in-hospital. The odds of ICU admission, mechanical ventilation, and death increased as the AKI stage worsened. Stage 3 AKI that occurred during hospitalization increased the odds of death (odds ratio [OR] = 7.87 [4.35, 14.23]). Stage 3 AKI that occurred prior to hospitalization carried an increased odds of death (OR = 5.28 [2.60, 10.73]). LIMITATIONS: Observational study with small sample size limits precision of estimates. Lack of nonhospitalized patients with COVID-19 and hospitalized patients without COVID-19 as controls limits causal inferences. CONCLUSIONS: Acute kidney injury, whether it occurs prior to or after hospitalization, is associated with a high risk of poor outcomes in patients with COVID-19. Routine assessment of kidney function in patients with COVID-19 may improve risk stratification. TRIAL REGISTRATION: The study was not registered on a publicly accessible registry because it did not involve any health care intervention on human participants.