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OBJECTIVES:. We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology. DESIGN:. Retrospective multicenter cohort studies of septic shock patients. SETTING:. All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion. PATIENTS:. Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10–8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity). CONCLUSIONS:. We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.

Introduction The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE.Methods and analysis REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial.Ethics and dissemination All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to – Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide.Trial registration number NCT03374800.

Objective To determine if the introduction of an emergency department (ED) sepsis screening tool and management bundle affects antibiotic prescribing and use.Design Multicentre, cohort, before-and-after study design.Setting Three tertiary hospitals in Queensland, Australia (median bed size 543, range 520–742).Participants Adult patients, presenting to the ED with symptoms and signs suggestive of sepsis who had blood cultures collected. These participants were further assessed and stratified as having septic shock, sepsis or infection alone, using Sepsis-3 definitions. The study dates were 1 July 2017–31 March 2020.Intervention The breakthrough series collaborative ‘Could this be Sepsis?’ Programme, aimed at embedding a sepsis screening tool and treatment bundle with weighted-incidence syndromic combined antibiogram-derived antibiotic guidelines in EDs.Main outcome measures The primary outcome was the rate of empirical prescriptions adherent to antibiotic guidelines during the ED encounter. Secondary outcomes included the empirical prescriptions considered appropriate, effective antibiotics administered within 3 hours and assessment of harm measures.Results Of 2591 eligible patients, 721 were randomly selected: 241 in the baseline phase and 480 in the post-intervention phase. The rates of guideline adherence were 54.0% and 59.5%, respectively (adjusted OR (aOR) 1.41 (95% CI 1.00, 1.98)). As compared with baseline, there was an increase in the rates of appropriate antibiotic prescription after bundle implementation (69.9% vs 57.1%, aOR 1.92 (95% CI 1.37, 2.68)). There were no differences between the baseline and post-intervention groups with respect to time to effective antibiotics, adverse effects or ED rates of broad-spectrum antibiotic use.Conclusion and relevance The use of an ED sepsis screening tool and management bundle was associated with an improvement in the rates of appropriate antibiotic prescription without evidence of adverse effects.

Abstract Background SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials. Methods ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined. Discussion This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Abstract Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Summary: Background: Sepsis bundles, promulgated by Surviving Sepsis Campaign have not been widely adopted because of variability in sepsis identification strategies, implementation challenges, concerns about excess antimicrobial use, and limited evidence of benefit. Methods: A 1-hour septic shock and a 3-hour sepsis bundle were implemented using a Breakthrough Series Collaborative in 14 public hospitals in Queensland, Australia. A before (baseline) and after (post-intervention) study evaluated its impact on outcomes and antimicrobial prescription in patients with confirmed bacteremia and sepsis. Findings: Between 01 July 2017 to 31 March 2020, of 6976 adults presenting to the Emergency Departments and had a blood culture taken, 1802 patients (732 baseline, 1070 post-intervention) met inclusion criteria. Time to antibiotics in 1-hour 73.7% vs 85.1% (OR 1.9 [95%CI 1.1-3.6]) and the 3-hour bundle compliance (48.2% to 63.3%, OR 1.7, [95%CI 1.4 to 2.1]) improved post-intervention, accompanied by a significant reduction in Intensive Care Unit (ICU) admission rates (26.5% vs 17.5% (OR 0.5, [95%CI 0.4 to 0.7]). There were no significant differences in-hospital and 30-day post discharge mortality between the two phases. In a post-hoc analysis of the post-intervention phase, sepsis pathway compliance was associated with lower in-hospital mortality (9.7% vs 14.9%, OR 0.6, 95%CI 0.4 to 0.8). The proportions of appropriate antimicrobial prescription at baseline and post-intervention respectively were 55.4% vs 64.1%, (OR 1.4 [95%CI 0.9 to 2.1]). Interpretation: Implementing 1-hour and 3-hour sepsis bundles for patients presenting with bacteremia resulted in improved bundle compliance and a reduced need for ICU admission without adversely influencing antimicrobial prescription. Funding: Queensland Health.

Abstract Background Randomised controlled trials (RCT) may be hindered by slow recruitment rates, particularly in critically ill patients. While statistical models to predict recruitment rates have been described, no systematic assessment has been conducted of the distribution of recruitment across sites, temporal trends in site participation and impact of competing trials on patient recruitment. Methods We used recruitment and screening logs from the SAFE, NICE-SUGAR, RENAL, CHEST and ADRENAL trials, five of the largest critical care RCTs. We quantified the extent of recruitment asymmetry between sites using Lorenz curves and Gini coefficients and assessed whether the recruitment distribution across sites follow the Pareto principle, which states that 80% of effects come from 20% of causes. Peak recruitment rates and growth in participating sites were calculated. Results In total, 25,412 patients were randomised in 99 intensive care units (ICUs) for the five trials. Distribution of recruitment was asymmetric, with a small number of ICUs recruiting a large proportion of the patients. The Gini coefficients ranged from 0.14 to 0.52. The time to peak recruitment rate ranged from 7 to 41 months and was variable (7, 31, 41, 10 and 40 months). Over time, the proportion of recruitment at non-tertiary ICUs increased from 15% to 34%. Conclusions There is asymmetry of recruitment with a small proportion of ICUs recruiting a large proportion of patients. The distributions of recruitment were not consistent with the Pareto principle. There has been increasing participation of non-tertiary ICUs in clinical trials.

OBJECTIVES:. To evaluate the implementation of a pediatric sepsis pathway in the emergency department as part of a statewide quality improvement initiative in Queensland, Australia. DESIGN:. Multicenter observational prospective cohort study. SETTING:. Twelve emergency departments in Queensland, Australia. PATIENTS:. Children less than 18 years evaluated for sepsis in the emergency department. Patients with signs of shock, nonshocked patients with signs of organ dysfunction, and patients without organ dysfunction were assessed. INTERVENTIONS:. Introduction of a pediatric sepsis pathway. MEASUREMENTS AND MAIN RESULTS:. Process measures included compliance with and timeliness of the sepsis bundle, and bundle components. Process and outcome measures of children admitted to the ICU with sepsis were compared with a baseline cohort. Five-hundred twenty-three children were treated for sepsis including 291 with suspected sepsis without organ dysfunction, 86 with sepsis-associated organ dysfunction, and 146 with septic shock. Twenty-four (5%) were admitted to ICU, and three (1%) died. The median time from sepsis recognition to bundle commencement for children with septic shock was 56 minutes (interquartile range, 36–99 min) and 47 minutes (interquartile range, 34–76 min) for children with sepsis-associated organ dysfunction without shock; 30% (n = 44) and 40% (n = 34), respectively, received the bundle within the target timeframe. In comparison with the baseline ICU cohort, bundle compliance improved from 27% (n = 45) to 58% (n = 14) within 60 minutes of recognition and from 47% (n = 78/167) to 75% (n = 18) within 180 minutes of recognition (p < 0.05). CONCLUSIONS:. Our findings on the introduction of protocolized care in a large and diverse state demonstrate ongoing variability in sepsis bundle compliance. Although bundle compliance improved compared with a baseline cohort, continued efforts are required to ensure guideline targets and sustainability are achieved.

Objective: Sepsis is responsible for a massive burden of disease, with a global estimate of 48.9 million cases resulting in approximately 11 million deaths annually. Survivors of sepsis may also experience long-term impairments that can persist for years after hospital discharge. These cognitive, physical and/or psychosocial deficits may contribute to a lower health related quality of life and represent a significant ongoing burden to the individual, the community and the health care system. We aim to systematically review the available evidence on long-term functional and quality of life outcomes after sepsis in children and adults.Data Sources: Medline, EMBASE, and CINAHL will be searched for eligible studies.Study Selection: Studies of adult and pediatric survivors of sepsis who had required admission to intensive care will be included. A minimum 6 month prospective follow up will be required. Accepted outcomes will be any validated measure of health-related quality of life (HRQoL) or functional deficits, using the Post-Intensive Care Syndrome (PICS) framework of cognitive, physical or psychosocial outcomes.Data Extraction: Data extraction will include information related to study characteristics, population characteristics, clinical criteria and outcomes.Data Synthesis: Studies meeting the inclusion criteria will be presented descriptively separated for pediatric and adult age groups. Meta-analysis will be attempted if sufficient primary data from several studies applying the same tests and outcomes are available. The primary outcome is HRQoL after sepsis; secondary outcomes include the functional status at follow-up.Conclusions: This systematic review will define the long-term impact of sepsis survivorship. The data will contribute to informing patient, clinician and stakeholder decisions and guide further research and resource management.