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Purpose To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. Methods The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1–2 who received invasive mechanical ventilation. Results 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO 2 /FiO 2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. Conclusions Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. Trial Registration: ClinicalTrials.gov NCT02010073.

IntroductionSepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome.Methods and analysisImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation.Ethics and disseminationThe protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d’éthique de la recherche sur l’être human of Switzerland. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04990232.

IntroductionOver half of patients who spend >48 hours in the intensive care unit (ICU) are fed via a nasogastric (NG) tube. Current guidance recommends continuous delivery of feed throughout the day and night. Emerging evidence from healthy human studies shows that NG feeding in an intermittent pattern (rather than continuous) promotes phasic hormonal, digestive and metabolic responses that are important for effective nutrition. It is not yet known whether this will translate to the critically ill population. Here, we present the protocol for a proof-of-concept study comparing diurnal intermittent vs continuous feeding on hormonal and metabolic outcomes for patients in the ICU.Methods and analysisThe study is a single-centre, prospective, randomised, open-label trial comparing intermittent enteral nutrition with the current standard practice of continuous enteral feeding. It aims to recruit participants (n=30) needing enteral nutrition via an NG tube for >24 hours who will be randomised to a diurnal intermittent or a continuous feeding regimen with equivalent nutritional value. The primary outcome is peak plasma insulin/c-peptide within 3 hours of delivering the morning intermittent feed on the second study day, compared with that seen in the continuous feed delivery group at the same time point. Secondary outcomes include feasibility, tolerability, efficacy and metabolic/hormonal profiles.Ethics and disseminationWe obtained ethical approval from the Wales Research Ethics Committee 3 prior to data collection (reference 23/WA/0297). We will publish the results of this study in an open-access peer-reviewed journal.Trial registration number NCT06115044.

IntroductionCritically ill patients often require enteral nutrition, but the optimal feeding strategy—continuous or intermittent—remains uncertain. While continuous enteral nutrition ensures steady nutrient delivery, it may inhibit key metabolic and cellular processes such as autophagy and ketogenesis. Intermittent enteral nutrition, by mimicking fasting periods, could activate protective pathways, potentially improving clinical outcomes. However, evidence for its efficacy and safety in intensive care units (ICUs) is limited. This study evaluates the clinical and metabolic impacts of fasting intervals during intermittent enteral nutrition compared with continuous enteral nutrition in critically ill patients.Methods and analysisWe designed a multicenter, randomised, open-label trial across nine French ICUs, enrolling adult patients requiring mechanical ventilation and vasopressor support. Participants will receive either intermittent or continuous enteral nutrition for 7 days, with the primary endpoint being the change in the Sequential Organ Failure Assessment (SOFA) score from Day 1 to Day 7 or ICU discharge. Secondary endpoints include nutritional intake, metabolic markers, gastrointestinal tolerance, ICU-acquired infections and mortality rates. Quality of life will be assessed at discharge. A total of 174 patients will be included. Descriptive statistics will summarise group characteristics, with the Student’s t-test or the Mann-Whitney U test depending on data distribution for SOFA score change, and regression for confounders. Secondary endpoints will be analysed using regression, χ2 or Fisher’s exact test, as appropriate.Ethics and disseminationThe study protocol was approved by a French ethics committee on 24 October 2023 (Comité de Protection des Personnes Ile de France 1, Paris, France, number SI 23.03427.000435). Patients are included after providing informed consent. Results will be submitted for publication in a peer-reviewed journal.Trial registration numberRegistered on clinicaltrials.gov on 26 March 2023 (NCT06330610).

BackgroundSevere pneumonia (SP) stands as one of the most prevalent critical illnesses encountered in clinical practice, characterised by its rapid onset and progression, numerous complications and elevated mortality rates. While modern medical interventions primarily focus on symptomatic management such as anti-infective therapy and mechanical ventilation, challenges including high drug resistance and suboptimal therapeutic outcomes for certain patients persist. Dry cupping as an ancient practice with over a millennium of clinical use in China is renowned for its convenience and perceived clinical efficacy in various illnesses. Nevertheless, the lack of well-designed studies assessing its effects remains a notable gap in the literature. This protocol describes a placebo-controlled, randomised, single-blind study to evaluate the efficacy and safety of dry cupping as an adjuvant treatment for SP.Methods and analysis66 patients diagnosed with SP, aged 18–80 years, will be randomly divided into two groups: intervention group, receiving 10 times of dry cupping treatment; control group, receiving placebo dry cupping therapy. Both applications are used in bilateral Fei Shu (BL13), Pi Shu (BL21) and Shen Shu (BL22) cupping. The application will be conducted once a day for 10 days. Participants will be assessed before treatment (D0), after the first intervention (D1), after the fifth intervention (D5) and after treatment ended (D10). The assessments include blood oxygen saturation, respiratory rate, traditional Chinese medicine symptom score, inflammatory response, mechanical ventilation time and oxygen condition.Ethics and disseminationThis protocol has been approved by the Ethics Committee of Shanghai Seventh People’s Hospital (2023-7th-HIBR-070). The results of the study will be disseminated to participants through social networks and will be submitted to a peer-reviewed journal and scientific meetings.Trial registration numberChiCTR2300076958.

IntroductionThere have been previous initiatives to identify key performance indicators (KPIs) for continuous kidney replacement therapy. However, no formal reviews of the evidence for KPIs of intermittent kidney replacement therapy (IKRT) have been conducted. This systematic review will appraise the evidence for KPIs of IKRT in critically ill patients and is part of the DIALYZING WISELY (NCT05186636) programme which aims to improve the performance of acute renal replacement therapy in intensive care units by aligning local practices with evidence-based best practices.Methods and analysisOvid MEDLINE, Ovid Embase, CINAHL and Cochrane Library will be searched for studies involving KPIs for IKRT. Grey literature will also be searched and include technical reports, practice guidelines and conference proceedings as well as websites of relevant organisations. We will search the Agency of Healthcare Research and National Quality Measures Clearinghouse for IKRT-related KPIs. Studies will be included if they contain KPIs, occur in critically ill patients and are associated with IKRT. We will evaluate the risk of bias using the modified Cochrane tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations methodology. The analysis will be primarily descriptive. Each KPI will be evaluated for importance, scientific acceptability, usability and feasibility using the four criteria proposed by the United States Strategic Framework Board for a National Quality Measurement and Reporting System. Finally, KPIs will be appraised for potential operational characteristics, potential to be integrated into electronic medical records, adoptability by stakeholders and affordability, if applicable.Ethics and disseminationEthics approval is not required as primary data will not be collected. Findings of this review will be disseminated through peer-related publication.PROSPERO registration numberCRD42022074444.

ObjectiveTo develop and validate a mechanical power (MP)-oriented prediction model of weaning failure in mechanically ventilated patients.DesignA retrospective cohort study.SettingData were collected from the large US Medical Information Mart for Intensive Care-IV (MIMIC-IV) V.1.0, which integrates comprehensive clinical data from 76 540 intensive care unit (ICU) admissions from 2008 to 2019.ParticipantsA total of 3695 patients with invasive mechanical ventilation for more than 24 hours and weaned with T-tube ventilation strategies were enrolled from the MIMIC-IV database.Primary and secondary outcomeWeaning failure.ResultsAll eligible patients were randomised into development cohorts (n=2586, 70%) and validation cohorts (n=1109, 30%). Multivariate logistic regression analysis of the development cohort showed that positive end-expiratory pressure, dynamic lung compliance, MP, inspired oxygen concentration, length of ICU stay and invasive mechanical ventilation duration were independent predictors of weaning failure. Calibration curves showed good correlation between predicted and observed outcomes. The prediction model showed accurate discrimination in the development and validation cohorts, with area under the receiver operating characteristic curve values of 0.828 (95% CI: 0.812 to 0.844) and 0.833 (95% CI: 0.809 to 0.857), respectively. Decision curve analysis indicated that the predictive model was clinically beneficial.ConclusionThe MP-oriented model of weaning failure accurately predicts the risk of weaning failure in mechanical ventilation patients and provides valuable information for clinicians making decisions on weaning.

ObjectivesTo explore the use, parameters, safety and outcomes of physical rehabilitation for adults with sepsis.DesignWe conducted a scoping review following the Joanna Briggs Institute framework.ParticipantsStudies were eligible for inclusion in the study if they included: (1) adults 18 and older, (2) with a previous diagnosis of sepsis, (3) using a physical rehabilitation intervention at any point of sepsis management, (4) published in English or French.ProcedureWe searched seven databases and screened titles and abstracts, reviewed full texts and performed data extraction independently and in duplicate. We summarised findings narratively using the “population, context, concept” framework and used descriptive statistics where appropriate. End-users reviewed and commented on study findings.ResultsWe included 58 studies, representing 77 434 participants, with the majority (79%) being published in the last decade. A large proportion (36%) of physical rehabilitation interventions included exercise and were overseen by a physical therapist (41%). The parameters of the interventions varied widely. However, all interventions (100%) were hospital based and the interventions implemented appeared safe. Of the 28 studies evaluating effectiveness of the intervention, function improved in most studies (78%) following physical rehabilitation.ConclusionResearch addressing physical rehabilitation for patients with sepsis is increasing. Physical rehabilitation appears safe and may improve functional outcomes in those with sepsis. Future research should report details of intervention parameters and evaluate rehabilitation post-hospital discharge to maximise impact on function and quality of life for sepsis survivors.RegistrationThe protocol was registered on Open Science Framework Registries (Registration DOI: https://doi.org/10.17605/OSF.IO/2EPJ6).

IntroductionSepsis is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes prompt antibiotics and intravenous fluids, facilitated by its early and accurate recognition. Currently, clinicians identify and assess severity of suspected sepsis using validated clinical scoring systems. In England, the National Early Warning Score 2 (NEWS2) has been mandated across all National Health Service (NHS) trusts and ambulance organisations. Like many clinical scoring systems, NEWS2 should not be used without clinical judgement to determine either the level of acuity or a diagnosis. Despite this, there is a tendency to overemphasise the score in isolation in patients with suspected infection, leading to the overprescription of antibiotics and potentially treatment-related complications and rising antimicrobial resistance. The biomarker procalcitonin (PCT) has been shown to be useful in specific circumstances to support appropriate antibiotics prescribing by identifying bacterial infection. PCT is not routinely used in the care of undifferentiated patients presenting to emergency departments (EDs), and the evidence base of its optimal usage is poor. The PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal (PRONTO) study is a randomised controlled trial (RCT) in adults with suspected sepsis presenting to the ED to compare standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment with standard clinical management based on NEWS2 scoring alone and compare if this approach reduces prescriptions of antibiotics without increasing mortality.Methods and analysisPRONTO is a parallel two-arm open-label individually RCT set in up to 20 NHS EDs in the UK with a target sample size of 7676 participants. Participants will be randomised in a ratio of 1:1 to standard clinical management based on NEWS2 scoring or standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment. We will compare whether the addition of PCT measurement to NEWS2 scoring can lead to a reduction in intravenous antibiotic initiation in ED patients managed as suspected sepsis, with at least no increase in 28-day mortality compared with NEWS2 scoring alone (in conjunction with local standard care pathways). PRONTO has two coprimary endpoints: initiation of intravenous antibiotics at 3 hours (superiority comparison) and 28-day mortality (non-inferiority comparison). The study has an internal pilot phase and group-sequential stopping rules for effectiveness and futility/safety, as well as a qualitative substudy and a health economic evaluation.Ethics and disseminationThe trial protocol was approved by the Health Research Authority (HRA) and NHS Research Ethics Committee (Wales REC 2, reference 20/WA/0058). In England and Wales, the law allows the use of deferred consent in approved research situations (including ED studies) where the time dependent nature of intervention would not allow true informed consent to be obtained. PRONTO has approval for a deferred consent process to be used. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences.Trial registration numberISRCTN54006056.

IntroductionIntubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation.Methods and analysisThe BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021.Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03928925).