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.).

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.

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.

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.

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.

Epigenetics of Sepsis.

OBJECTIVES: Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures. DATA SOURCES: Online search of published scientific literature via Pubmed using the term "epigenetics" in combination with the terms "sepsis", "infection", "bacterial infection", "viral infection", "critical illness", "acute respiratory distress syndrome", and "acute lung injury". STUDY SELECTION: Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles. DATA EXTRACTION: Relevant data was extracted and synthesized for narrative review. DATA SYNTHESIS: Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1ß. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury. CONCLUSIONS: Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers.

Epigenetic Profiling in Severe Sepsis: A Pilot Study of DNA Methylation Profiles in Critical Illness.

OBJECTIVES: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. DESIGN: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on "Day 1" of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as ß values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. SETTING: Tertiary care hospitals. SUBJECTS: Critically ill septic and nonseptic patients. INTERVENTIONS: Observational study. MEASUREMENTS AND MAIN RESULTS: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR ß I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ ß I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region-associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. CONCLUSIONS: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis.

DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.

RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.

Activated neutrophils induce epithelial cell apoptosis through oxidant-dependent tyrosine dephosphorylation of caspase-8.

Activated neutrophils can injure host cells through direct effects of oxidants on membrane phospholipids, but an ability to induce apoptotic cell death has not previously been reported. We show that neutrophils activated in vivo in patients who have sustained multiple trauma or in vitro by exposure to bacterial lipopolysaccharide promote epithelial cell apoptosis through SHP-1-mediated dephosphorylation of epithelial cell caspase-8. Epithelial cell apoptosis induced by circulating neutrophils from patients who had sustained serious injury depended on the generation of neutrophil-derived reactive oxygen intermediates and was blocked by inhibition of NADPH oxidase or restoration of intracellular glutathione. Caspase-8 was constitutively tyrosine phosphorylated in a panel of resting epithelial cells, but underwent SHP-1-dependent dephosphorylation in response to hydrogen peroxide, activated neutrophils, or inhibition of Src kinases. Cells transfected with a mutant caspase-8 in which tyrosine residues at Tyr397 or Tyr465 are replaced by nonphosphorylatable phenylalanine underwent accelerated apoptosis, whereas either mutation of these residues to phosphomimetic glutamic acid or transfection with the Src kinases Lyn or c-Src inhibited hydrogen peroxide-induced apoptosis. Exposure to either hydrogen peroxide or lipopolysaccharide-stimulated neutrophils increased phosphorylation and activity of the phosphatase SHP-1, increased activity of caspases 8 and 3, and accelerated epithelial cell apoptosis. These observations reveal a novel mechanism for neutrophil-mediated tissue injury through oxidant-dependent, SHP-1-mediated dephosphorylation of caspase-8 resulting in enhanced epithelial cell apoptosis.

Biomarkers in acute respiratory distress syndrome.

PURPOSE OF REVIEW: The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area. RECENT FINDINGS: Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the 'troponin' of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome. SUMMARY: This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation.

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.

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.

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).

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.

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.