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Background & Purpose: In response to the multitude of ethical issues that arise in the delivery of care provided in intensive care units (ICUs), nurses working in this setting frequently experience moral distress. The properties of moral distress have been well defined. However, within the context of the coronavirus-disease 2019 (COVID-19) pandemic, less is known about the properties of moral distress experienced by ICU nurses. This subsequently affects the advancement of our knowledge, specifically of effective mitigative interventions for moral distress. The purpose of this analysis is to describe the key properties of moral distress experienced by ICU nurses during the COVID-19 pandemic. Methods & Procedures: Guided by interpretive descriptive design, a purposeful sample of 40 Canadian ICU nurses described their experiences of moral distress within the context of their practice during the COVID-19 pandemic. Data generated included the administration of a demographic questionnaire and the Measure of Moral Distress - Healthcare Providers survey, and 1:1 semi-structured virtual (telephone or videoconference) interviews (May–September 2021). Analysis was informed by the tenents of reflexive thematic analysis and rapid qualitative analysis. Results: Nurses experienced moral distress under the complex interplay of two overarching, broad conditions: (1) when nurses’ voices, driven by efforts to optimize patient care at an exceptionally high standard, were not heard; and (2) when patients received substandard levels of care, that was not patient-centered, pain free, or that did not align with organizational, professional, or personal standards. These two broad conditions were influenced by three sub-conditions: (1) lack of respect for nurses’ expert knowledge; (2) cultures and systems of communication and (3) responses to safety and staffing. Discussion: Moral distress experienced by Canadian ICU nurses is a complex phenomenon. These findings advance and refine our knowledge of key components of moral distress. We identified the conditions that generate moral distress for nurses, and the properties of the antecedent moral events. Future approaches to mitigate moral distress need to address the broad conditions under which moral distress occurs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-1β), 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 ). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rationale: The end of life (EOL) experience in the intensive care unit (ICU) can be psychologically distressing for patients, families, and clinicians. The 3 Wishes Project (3WP) personalizes the EOL experience by carrying out wishes for dying patients and their families. While the 3WP has been integrated in academic, tertiary care ICUs, implementing this project in a community ICU has yet to be described. Objectives: To examine facilitators of, and barriers to, implementing the 3WP in a community ICU from the clinician and implementation team perspective. Methods: This qualitative descriptive study evaluated the implementation of the 3WP in a 20‐bed community ICU in Southern Ontario, Canada. Patients were considered for the 3WP if they had a high likelihood of imminent death or planned withdrawal of life‐sustaining therapy. Following the qualitative descriptive approach, semi‐structured interviews were conducted with purposively sampled clinicians and implementation team. Data from transcribed interviews were analyzed in triplicate through qualitative content analysis. Results: Interviews with 12 participants indicated that the 3WP personalized and enriched the EOL experience. Interviewees indicated higher intensity education strategies were needed to enable spread as the project grew. Clinicians described many physical resources for the project but suggested more non‐clinical project support for orientation, continuing education, and data collection. A majority of wishes focused on physical resources including keepsakes, which helped facilitate project spread when clinician capacity was attenuated by competing duties. Conclusions: In this community hospital, ICU clinicians and implementation team members report perceived improved EOL care for patients, families, and clinicians following 3WP initiation and integration. Implementing individualized and meaningful wishes at EOL for dying patients in a community ICU requires adequate planning and time dedicated to optimizing clinician education. Adapting key features of an intervention to local expertise and capacity may facilitate spread during project initiation and integration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-1β. 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. [ABSTRACT FROM AUTHOR]

Introduction Diarrhoea is a frequent concern in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, increased length of ICU stay, skin breakdown and renal dysfunction. However, its prevalence, aetiology and prognosis in the critically ill have been poorly studied. The primary objectives of this study are to determine the incidence, risk factors and consequences of diarrhoea in critically ill adults. The secondary objectives are to estimate the incidence of Clostridium difficileassociated diarrhoea (CDAD) in ICU patients and to validate the Bristol Stool Chart and Bliss Stool Classification System characterising bowel movements in the ICU. Our primary outcome is the incidence of diarrhoea . Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay. Methods and analysis This international prospective cohort study will enrol patients over 10 weeks in 12 ICUs in Canada, the USA, Poland and Saudi Arabia. We will include all patients 18 years of age and older who are admitted to the ICU for at least 24 hours and follow them daily until ICU discharge. Our primary outcome is the incidence of diarrhoea based on the WHO definition, during the ICU stay. Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay. We will use logistic regression to identify factors associated with diarrhoea (as defined using WHO criteria) and the kappa statistic to measure agreement on diarrhoea rates between the WHO definition and the Bristol Stool Chart and Bliss Stool Classification System. Ethics and dissemination The protocol has been approved by the research ethics board of all participating centres. The diarrhoea interventions, consequences and epidemiology in the intensive care unit (DICE-ICU) study will generate evidence about diarrhoea and its frequency, predisposing factors and consequences, to inform critical care practice and future research. Lay summary Diarrhoea is a frequent clinical problem for hospitalised patients including those who are critically ill in the ICU. Diarrhoea can cause complications such as skin damage, dehydration and kidney problems. It is not clear how common diarrhoea is in the ICU, the factors that cause it or the best way for clinicians to assess it. The DICE-ICU study is an international prospective observational study to examine the frequency, risk factors and outcomes of diarrhoea during critical illness. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to explore the experiences, beliefs and perceptions of intensive care unit (ICU) nurses on the management of pain, agitation and delirium (PAD) in critically ill patients. Design A qualitative descriptive study. Setting This study took place in a community hospital ICU located in a medium size Canadian city. Participants Purposeful sampling was conducted. Participants included full-time nurses working in the ICU. Forty-six ICU nurses participated. Methods A total of five focus group sessions were held to collect data. There were one to three separate groups in each focus group session, with no more than seven participants in each group. There were 10 separate groups in total. A semistructured question guide was used. Thematic analysis method was adopted to analyse the data, and to search for emergent themes and patterns. Results Three main themes emerged: (1) the professional perspectives on patient wakefulness state, (2) the professional perspectives on PAD management of critically ill patients and (3) the factors impacting PAD management. Nurses have different opinions on the optimal level of patient sedation and felt that many factors, including environmental, healthcare teams, patients and family members, can influence PAD management. This potentially leads to inconsistent PAD management in critically ill patients. The nurses also believed that PAD management requires a multidisciplinary approach including healthcare teams and patients' families. Conclusions Many external and internal factors contribute to the complexity of PAD management including the attitudes of nursing staff towards PAD. The themes emerged from this study suggested the need of a multifaceted and multidisciplinary quality improvement programme to optimise the management of PAD in the ICU. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Legionella pneumophila, a major cause of Legionnaires' disease, accounts for 2-15 % of all communityacquired pneumonia requiring hospitalization and up to 30 % of community-acquired pneumonia requiring intensive care unit admission. Early initiation of appropriate antimicrobial therapy is a crucial step in the prevention of morbidity and mortality. However, recognition of Legionnaires' disease continues to be challenging because of its nonspecific clinical features. We sought to describe hospitalized community-acquired Legionnaires' disease to increase awareness of this important and potentially lethal disease. Methods: A retrospective multicenter observational study was conducted with all patients with confirmed Legionnaires' disease in the Niagara Region of the Province of Ontario, Canada, from June to December 2013. Results: From June to December 2013, there were 14 hospitalized cases of Legionnaires' disease in the Niagara Region. Of these, 86 % (12 patients) had at least one comorbidity and 71 % (10 patients) were cigarette smokers. In our cohort, Legionnaires' disease was diagnosed with a combination of a urinary Legionella antigen test and a Legionella real-time polymerase chain reaction assay. Delay in effective antimicrobial therapy in the treatment of Legionella infection led to clinical deterioration. The majority of patients had met systemic inflammatory response syndrome criteria with fever >38 °C (71 %), heart rate >90 beats per minute (71 %), and respiratory rate >20 breaths per minute (86 %). Eleven patients (79 %) required admission to the intensive care unit or step-down unit, and nine patients (64 %) required intubation. Clinical improvement after initiation of antimicrobials was protracted. Conclusions: Legionnaires' disease should be considered during the late spring and summer months in patients with a history of tobacco use and various comorbidities. Clinically, patients presented with severe, nonspecific, multisystem disease characterized by shortness of breath, abnormal vital signs, and laboratory derangements including hyponatremia, elevated creatine kinase, and evidence of organ dysfunction. In addition, antimicrobial therapy with newer macrolides or respiratory fluoroquinolones should be initiated for severe community-acquired pneumonia requiring intensive care unit admission, prior to laboratory confirmation of diagnosis, especially when a clinical suspicion of Legionella infection exists. [ABSTRACT FROM AUTHOR]

Introduction: Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart-lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies.Case Presentation: We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient.Conclusions: High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy. [ABSTRACT FROM AUTHOR]

Background: Diisopropyl fluorophosphate (DFP) is a serine protease inhibitor that is widely used as an inhibitor of endogenous proteases in in vitro neutrophil studies. Its effects on neutrophil function are unclear. We sought to determine the biological effects of DFP on human neutrophil apoptosis and oxidative burst. Methods: We isolated neutrophils from healthy volunteers, incubated them with DFP (2.5 mM), and evaluated neutrophil elastase (NE) activity, neutrophil degranulation, apoptosis as reflected in hypodiploid DNA formation and exteriorization of phosphatidylserine (PS), processing and activity of caspases-3 and -8, oxidative burst activity and hydrogen peroxide release. Results: Consistent with its activity as a serine protease inhibitor, DFP significantly inhibited NE activity but not the degranulation of azurophilic granules. DFP inhibited constitutive neutrophil apoptosis as reflected in DNA fragmentation, and the processing and activity of caspases-3 and -8. DFP also inhibited priming of neutrophils for oxidative burst activity and hydrogen peroxide release. However, DFP enhanced the exteriorization of PS in a dose-dependent manner. Conclusion: We conclude that DFP exerts significant effects on neutrophil inflammatory function that may confound the interpretation of studies that use it for its antiprotease activity. We further conclude that endogenous proteases play a role in the biology of constitutive neutrophil apoptosis. [ABSTRACT FROM AUTHOR]