Evaluating the impact of a SIMPlified LaYered consent process on recruitment of potential participants to the Staphylococcus aureus Network Adaptive Platform trial: study protocol for a multicentre pragmatic nested randomised clinical trial (SIMPLY-SNAP trial).

INTRODUCTION: Informed consent forms (ICFs) for randomised clinical trials (RCTs) can be onerous and lengthy. The process has the potential to overwhelm patients with information, leading them to miss elements of the study that are critical for an informed decision. Specifically, overly long and complicated ICFs have the potential to increase barriers to trial participation for patients with mild cognitive impairment, those who do not speak English as a first language or among those with lower medical literacy. In turn, this can influence trial recruitment, completion and external validity. METHODS AND ANALYSIS: SIMPLY-SNAP is a pragmatic, multicentre, open-label, two-arm parallel-group superiority RCT, nested within a larger trial, the Staphylococcus aureus Network Adaptive Platform (SNAP) trial. We will randomise potentially eligible participants of the SNAP trial 1:1 to a full-length ICF or a SIMPlified LaYered (SIMPLY) consent process where basic information is summarised with embedded hyperlinks to supplemental information and videos. The primary outcome is recruitment into the SNAP trial. Secondary outcomes include patient understanding of the clinical trial, patient and research staff satisfaction with the consent process, and time taken for consent. As an exploratory outcome, we will also compare measures of diversity (eg, gender, ethnicity), according to the consent process randomised to. The planned sample size will be 346 participants. ETHICS AND DISSEMINATION: The study has been approved by the ethics review board (Sunnybrook Health Sciences Research Ethics Board) at sites in Ontario. We will disseminate study results via the SNAP trial group and other collaborating clinical trial networks. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT06168474; www. CLINICALTRIALS: gov).

A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial.

Background: The burden of sepsis is high in India and is associated with substantial morbidity and mortality. Vitamin C, an endogenous antioxidant, may improve patient outcomes. Methods: This was a parallel-group pilot feasibility randomized controlled trial conducted at 2 intensive care units in India. Adult patients (≥18 years) with proven or suspected infection as the main diagnosis and needing a continuous intravenous vasopressor infusion were randomized to intravenous vitamin C (50 mg/kg every 6 hours for a maximum of 16 doses) or matching placebo. Primary outcomes were related to protocol adherence and feasibility (enrollment per month). The key secondary outcome was the composite of mortality or persistent organ dysfunction (POD) at day 28 after randomization. Results: 60 patients were screened, 51 were eligible, 32 were randomized, and 30 were included in the analysis (randomized/eligible ratio: 0.63). The overall rate of enrollment was 1.5 patients per month. The median (IQR) age was 63.5 (51.0, 70.0) and 70.0% of the patients were male. In both arms, all patients received ≥90% of scheduled doses of the study drug. No patient received open-label vitamin C and there were no deviations from the glucose monitoring protocol. The composite outcome of mortality or POD at day 28 occurred in 56.3% (9/16) in the vitamin C arm as compared to 42.9% (6/14) in the placebo arm [RR: 1.31 (95% CI: 0.62, 2.76), p = 0.47]. Conclusion: In this pilot feasibility randomized controlled trial of vitamin C for adult patients with sepsis, protocol adherence was excellent and feasibility endpoints were met. Trial registration: CTRI/2020/03/024371. How to cite this article: Vijayaraghavan BKT, Venkataraman R, Ramanathan Y, Margabandhu S, Jayakumar D, Ramachandran P, et al. A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial. Indian J Crit Care Med 2023;27(12):910-916.

Antibiotic treatment durations for pyogenic liver abscesses: A systematic review.

Background: We sought to systematically review the existing research on pyogenic liver abscesses to determine what data exist on antibiotic treatment durations. Methods: We conducted a systematic review and meta-analysis of contemporary medical literature from 2000 to 2020, searching for studies of pyogenic liver abscesses. The primary outcome of interest was mean antibiotic treatment duration, which we pooled by random-effects meta-analysis. Meta-regression was performed to examine characteristics influencing antibiotic durations. Results: Sixteen studies (of 3,933 patients) provided sufficient data on antibiotic durations for pooling in meta-analysis. Mean antibiotic durations were highly variable across studies, from 8.4 (SD 5.3) to 68.9 (SD 30.3) days. The pooled mean treatment duration was 32.7 days (95% CI 24.9 to 40.6), but heterogeneity was very high (I2 = 100%). In meta-regression, there was a non-significant trend towards decreased mean antibiotic treatment durations over later study years (-1.14 days/study year [95% CI -2.74 to 0.45], p = 0.16). Mean treatment duration was not associated with mean age of participants, percentage of infections caused by Klebsiella spp, percentage of patients with abscesses over 5 cm in diameter, percentage of patients with multiple abscesses, and percentage of patients receiving medical management. No randomized trials have compared treatment durations for pyogenic liver abscess, and no observational studies have reported outcomes according to treatment duration. Conclusions: Among studies reporting on antibiotic durations for pyogenic liver abscess, treatment practices are highly variable. This variability does not seem to be explained by differences in patient, pathogen, abscess, or management characteristics. Future RCTs are needed to guide optimal treatment duration for patients with this complex infection.

Historique: Les chercheurs ont procédé à l'analyse systématique des recherches sur les abcès hépatiques pyogènes afin de découvrir les données sur la durée de l'antibiothérapie. Méthodologie: Les chercheurs ont réalisé une analyse systématique et une méta-analyse des publications médicales parues entre 2000 et 2020 pour en extraire les études sur les abcès hépatiques pyogènes. Le résultat primaire était la durée moyenne de l'antibiothérapie, qu'ils ont regroupée par méta-analyse à effets aléatoires. Ils ont procédé à une méta-régression pour examiner les caractéristiques qui influent sur la durée de l'antibiothérapie. Résultats: Seize études (auprès de 3 933 patients) contenaient assez de données sur la durée de l'antibiothérapie pour être regroupées dans la méta-analyse. La durée moyenne de l'antibiothérapie était très variable d'une étude à l'autre, de 8,4±5,3 à 68,9±30,3 jours. La durée moyenne du traitement regroupé était de 32,7 jours (IC à 95 %, 24,9 à 40,6 jours), mais l'hétérogénéité était très élevée (I2 = 100 %). La méta-régression a révélé une tendance non significative vers une durée moins longue de l'antibiothérapie moyenne pendant les dernières années de l'étude (−1,14 jour par année d'étude, IC à 95 %, −2,74+0,45, p = 0,16). La durée moyenne du traitement n'était pas associée à l'âge moyen des participants, au pourcentage d'infections causées par les espèces de Klebsiella, au pourcentage de patients ayant un abcès de plus de cinq centimètres de diamètre, au pourcentage de patients ayant de multiples abcès et au pourcentage de patients recevant une prise en charge médicale. Aucune étude randomisée n'avait comparé la durée du traitement de l'abcès hépatique pyogène, et aucune étude observationnelle n'avait rendu compte des résultats cliniques en fonction de la durée du traitement. Conclusions: Dans les études sur la durée de l'antibiothérapie des abcès hépatiques pyogènes, les pratiques thérapeutiques sont très variables. Cette variabilité ne semble pas s'expliquer par les différences entre les patients, les agents pathogènes, les abcès ou les caractéristiques de prise en charge. Des études randomisées et contrôlées devront être réalisées pour obtenir des indications quant à la durée optimale du traitement chez les patients atteints de cette infection complexe.

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Fixed versus individualized treatment for five common bacterial infectious syndromes: a survey of the perspectives and practices of clinicians.

Background: Traditionally, bacterial infections have been treated with fixed-duration antibiotic courses; however, some have advocated for individualized durations. It is not known which approach currently predominates. Methods: We conducted a multinational clinical practice survey asking prescribers their approach to treating skin and soft tissue infection (SSTI), community-acquired pneumonia (CAP), pyelonephritis, cholangitis and bloodstream infection (BSI) of an unknown source. The primary outcome was self-reported treatment approach as being fully fixed duration, fixed minimum, fixed maximum, fixed minimum and maximum, or fully individualized durations. Secondary questions explored factors influencing duration of therapy. Multivariable logistic regression with generalized estimating equations was used to examine predictors of use of fully fixed durations. Results: Among 221 respondents, 170 (76.9%) completed the full survey; infectious diseases physicians accounted for 60.6%. Use of a fully fixed duration was least common for SSTI (8.5%) and more common for CAP (28.3%), BSI (29.9%), cholangitis (35.7%) and pyelonephritis (36.3%). Fully individualized therapy, with no fixed minimum or maximum, was used by only a minority: CAP (4.9%), pyelonephritis (5.0%), cholangitis (9.9%), BSI (13.6%) and SSTI (19.5%). In multivariable analyses, a fully fixed duration approach was more common among Canadian respondents [adjusted OR (aOR) 1.76 (95% CI 1.12-2.76)] and for CAP (aOR 4.25, 95% CI 2.53-7.13), cholangitis (aOR 6.01, 95% CI 3.49-10.36), pyelonephritis (aOR 6.08, 95% CI 3.56-10.39) and BSI (aOR 4.49, 95% CI 2.50-8.09) compared with SSTI. Conclusions: There is extensive practice heterogeneity in fixed versus individualized treatment; clinical trials would be helpful to compare these approaches.

Does this patient have Clostridioides difficile infection? A systematic review and meta-analysis.

BACKGROUND: The clinical features and predictors of Clostridioides difficile infection overlap with many conditions. OBJECTIVES: We performed a systematic review to evaluate the diagnostic utility of clinical features (clinical examination, risk factors, laboratory tests, and radiographic findings) associated with C. difficile. METHODS: Systematic review and meta-analysis of diagnostic features for C. difficile. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Cochrane databases were searched up to September 2021. STUDY ELIGIBILITY CRITERIA: Studies that reported clinical features of C. difficile, a valid reference standard test for confirming diagnosis of C. difficile, and a comparison among patients with a positive and negative test result. PARTICIPANTS: Adult and paediatric patients across diverse clinical settings. OUTCOMES: Sensitivity, specificity, likelihood ratios. REFERENCE STANDARD: Stool nucleic acid amplification tests, enzyme immunoassays, cell cytotoxicity assay, and stool toxigenic culture. ASSESSMENT OF RISK OF BIAS: Rational Clinical Examination Series and Quality Assessment of Diagnostic Accuracy Studies-2. METHODS OF DATA SYNTHESIS: Univariate and bivariate analyses. RESULTS: We screened 11 231 articles of which 40 were included, enabling the evaluation of 66 features for their diagnostic utility for C. difficile (10 clinical examination findings, 4 laboratory tests, 10 radiographic findings, prior exposure to 13 antibiotic types, and 29 clinical risk factors). Of the ten features identified on clinical examination, none were significantly clinically associated with increased likelihood of C. difficile infection. Some features that increased likelihood of C. difficile infection were stool leukocytes (LR+ 5.31, 95% CI 3.29-8.56) and hospital admission in the prior 3 months (LR+ 2.14, 95% CI 1.48-3.11). Several radiographic findings also strongly increased the likelihood of C. difficile infection like ascites (LR+ 2.91, 95% CI 1.89-4.49). DISCUSSION: There is limited utility of bedside clinical examination alone in detecting C. difficile infection. Accurate diagnosis of C. difficile infection requires thoughtful clinical assessment for interpretation of microbiologic testing in all suspected cases.

Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial.

INTRODUCTION: The BALANCE study is a randomised clinical trial (3626 participants) designed to assess the non-inferiority of 7 days (short-course) antibiotic therapy compared with 14 days of therapy for bacteraemia using the pragmatic endpoint of 90-day survival. Based on pilot study data, approximately 30% of enrolees will have a urinary tract infection (UTI) as the source of bacteraemia. METHODS AND ANALYSIS: We aim to assess the non-inferiority of short-course antibiotic therapy for patients with bacteraemia UTIs.Participating sites in four countries will be invited to join this substudy. All participants of this substudy will be enrolled in the main BALANCE study. The intervention will be assigned and treatment administered as specified in the main protocol.We will include participants in this substudy if the probable source of their infection is a UTI, as judged by the site principal investigator, and they have a urine microscopy and culture indicative of a UTI. Participants will be excluded if they have an ileal loop, vesicoureteric reflux or suspected or confirmed prostatitis.The primary outcome is the absence of a positive culture on a test-of-cure urine sample collected 6-12 days after cessation of antimicrobials, with a non-inferiority margin of 15%. Secondary outcomes include the clinical resolution of infection symptoms at test-of-cure. ETHICS AND DISSEMINATION: The study has been approved in conjunction with the main BALANCE study through the relevant ethics review process at each participating site. We will disseminate the results through the Australasian Society for Infectious Diseases, Canadian Critical Care Trials Group, the Association for Medical Microbiology and Infectious Diseases Canada Clinical Research Network (AMMI Canada CRN) and other collaborators. UNIVERSAL TRIAL NUMBER: U1111-1256-0874. MAIN BALANCE TRIAL REGISTRATION: NCT03005145. TRIAL REGISTRATION NUMBER: Australian Clinical Trial Register: ACTRN12620001108909.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134. FINDINGS: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (pinteraction=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. INTERPRETATION: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated. FUNDING: EU-RESPONSE.

New and Persistent Sedative Prescriptions Among Older Adults Following a Critical Illness: A Population-Based Cohort Study.

BACKGROUND: ICU survivors often have complex care needs and can experience insufficient medication reconciliation and polypharmacy. It is unknown which ICU survivors are at risk of new sedative use posthospitalization. RESEARCH QUESTION: For sedative-naive, older adult ICU survivors, how common is receipt of new and persistent sedative prescriptions, and what factors are associated with receipt? STUDY DESIGN AND METHODS: This population-based cohort study included ICU survivors aged ≥ 66 years who had not filled sedative prescriptions within ≤ 6 months before hospitalization (sedative-naive) in Ontario, Canada (2003-2019). Using multilevel logistic regression, demographic, clinical, and hospital characteristics and their association with new sedative prescription within ≤ 7 days of discharge are described. Variation between hospitals was quantified by using the adjusted median OR. Factors associated with persistent prescriptions (≤ 6 months) were examined with a multivariable proportional hazards model. RESULTS: A total of 250,428 patients were included (mean age, 76 years; 61% male). A total of 15,277 (6.1%) filled a new sedative prescription, with variation noted across hospitals (2% [95% CI, 1-3] to 44% [95% CI, 3-57]); 8,458 (3.4%) filled persistent sedative prescriptions. Adjusted factors associated with a new sedative included: discharge to long-term care facility (adjusted OR [aOR], 4.00; 95% CI, 3.72-4.31), receipt of inpatient geriatric (aOR, 1.95; 95% CI, 1.80-2.10) or psychiatry (aOR, 2.76; 95% CI, 2.62-2.91) consultation, invasive ventilation (aOR, 1.59; 95% CI, 1.53-1.66), and ICU length of stay ≥ 7 days (aOR, 1.50; 95% CI, 1.42-1.58). The residual heterogeneity between hospitals (adjusted median OR, 1.43; 95% CI, 1.35-1.49) had a stronger association with new sedative prescriptions than the Charlson Comorbidity Index score or sepsis. Factors associated with persistent sedative use were similar with the addition of female subjects (subdistribution hazard ratio, 1.07; 95% CI, 1.02-1.13) and pre-existing polypharmacy (subdistribution hazard ratio, 0.88; 95% CI, 0.80-0.93). INTERPRETATION: One in 15 sedative-naive, older adult ICU survivors filled a new sedative within ≤ 7 days of discharge; more than one-half of these survivors filled persistent prescriptions. New prescriptions at discharge varied widely across hospitals and represent the potential value of modifying prescription practices, including medication review and reconciliation.

Effect of video camera monitoring feedback on hand hygiene compliance in neonatal intensive care unit, an interventional study.

BACKGROUND: The purpose of this study was to determine whether use of a video camera surveillance system for hand hygiene (HH) monitoring, video-based education, and feedback could improve the HH compliance in a neonatal intensive care unit (NICU). METHODS AND MATERIALS: This was an interventional before-after trial conducted in a level-III NICU between July 2019 and June 2020. HH compliance was measured using randomly selected video-camera footage in the baseline, intervention, and maintenance periods. After the baseline, an intervention consisting of feedback and education with video scenarios was implemented. The primary outcome was change in HH compliance. The compliance rates were analyzed as an interrupted time series (ITS) with a segmented regression model adjusted for autocorrelation for each study period. RESULTS: We identified a total of 8335 HH indications. There were non significant increases in the total compliance rate (9.0%, 95% CI -2% to 20%) at the time of intervention and in the compliance rate after intervention (0.26%, 95% CI -0.31% to 0.84%) per day. The hand hygiene compliance before patient contact significantly increased (19.8%, 95% CI, 4.8%-34.8%). Incorrect glove use improved non-significantly with the intervention (-3.4%, 95% CI -13.4% to 6.7%). CONCLUSION: In this study of HH monitoring using video-camera footage combined with an intervention including feedback and education, there were inconsistent improvements in HH compliance. However, these improvements were not sustained in the long term. Frequent feedback and education may be required to sustain high compliance.

Prognostic Factors Associated With Extubation Failure in Acutely Brain-Injured Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Extubation failure in brain-injured patients is associated with increased morbidity. Our objective was to systematically review prognostic factors associated with extubation failure in acutely brain-injured adult patients receiving invasive ventilation in an ICU. DATA SOURCES: MEDLINE, Embase, and Cochrane Central were searched from inception to January 31, 2022. STUDY SELECTION: Two reviewers independently screened citations and selected English-language cohort studies and randomized trials examining the association of prognostic factors with extubation failure. Studies were considered if they included greater than or equal to 80% adult patients with acute brain injury admitted to the ICU and mechanically ventilated for greater than or equal to 24 hours. DATA EXTRACTION: Two reviewers extracted data on population, prognostic factors, extubation outcomes, and risk of bias (using the quality in prognostic factors tool). DATA SYNTHESIS: In the primary analysis, adjusted odds ratios (aOR) for each prognostic factor were pooled using random-effects models. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The search identified 7,626 citations, of which 21 studies met selection criteria. Moderate-certainty evidence suggested increased risk of extubation failure with older age (aOR, 3.0 for upper vs lower tertile; 95% CI, 1.78-5.07) and longer duration of mechanical ventilation (aOR, 3.47 for upper vs lower tertile; 95% CI, 1.68-7.19). Presence of cough (aOR, 0.40; 95% CI, 0.28-0.57) and intact swallow (aOR, 0.34; 95% CI, 0.21-0.54) probably decreased risk of extubation failure (moderate certainty). Associations of other factors with extubation failure were informed by low or very low certainty evidence. CONCLUSIONS: Patient age, duration of mechanical ventilation, and airway reflexes were associated with extubation failure in brain-injured patients with moderate certainty. Future studies are needed to determine the optimal application of these variables in clinical practice.

Defibrillation Strategies for Refractory Ventricular Fibrillation.

BACKGROUND: Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation. METHODS: We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge. RESULTS: A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively). CONCLUSIONS: Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).

Prevalence and predictors of persistent post-COVID-19 symptoms.

BACKGROUND: The pandemic has affected hundreds of millions of people; early reports suggesting high rates of prolonged symptoms may be prone to selection bias. METHODS: In a program caring for all SARS-CoV-2 positive inpatients and outpatients between March to October 2020, and offering universal 90-day follow-up, we compared those who died prior to 90 days, not responding to follow-up, declining, or accepting follow-up. Among those seen or declining follow-up, we determined the prevalence and predictors of persistent symptoms. RESULTS: Among 993 patients, 21 (2.1%) died prior to 90 days, 506 (50.9%) did not respond, 260 (26.1%) declined follow-up because they were well, and 206 (20.7%) were fully assessed. Of 466 who responded to follow-up inquiry, 133 (28.5%) reported ≥1 persistent symptom, including constitutional (15.5%), psychiatric (14.2%), rheumatologic (13.1%), neurologic (13.1%), cardiorespiratory (12.0%), and gastrointestinal (1.7%). Predictors differed for each symptom type. Any persistent symptom was more common in older patients (adjusted odds ratio [aOR] 1.11, 95% CI 1.04 to 1.18/5 years), those diagnosed in hospital (aOR 2.03, 95% CI 1.24 to 3.33) and those with initial constitutional and rheumatologic symptoms. Patients not responding to follow-up were younger and healthier at baseline. CONCLUSION: Persistent symptoms are common and diverse 3 months post-COVID-19 but are likely over-estimated by most reports.

HISTORIQUE: La pandémie touche des centaines de millions de gens. Les rapports précoces laissant croire à des symptômes prolongés pourraient être assujettis à un biais de sélection. MÉTHODOLOGIE: Dans un programme de soins auprès de tous les patients ambulatoires et hospitalisés ayant reçu un résultat positif au SRAS-CoV-2 entre mars et octobre 2020, assorti d'un suivi universel de 90 jours, les chercheurs ont comparé les personnes qui ont succombé avant 90 jours, n'ont pas répondu au suivi ou ont décliné ou accepté le suivi. Chez celles qui ont été vues ou ont décliné le suivi, ils ont déterminé la prévalence et les prédicteurs de symptômes persistants. RÉSULTATS: Chez les 993 patients, 21 (2,1 %) sont décédés avant les 90 jours, 506 (50,9 %) n'ont pas répondu, 260 (26,1 %) ont décliné le suivi parce qu'ils se sentaient bien et 206 (20,7 %) se sont soumis à une évaluation complète. Des 466 qui ont répondu à l'offre de suivi, 133 (28,5 %) ont signalé ressentir au moins un symptôme persistant, y compris d'ordre constitutionnel (15,5 %), psychiatrique (14,2 %), rhumatologique (13,1 %), neurologique (13,1 %), cardiorespiratoire (12,0 %) et gastro-intestinal (1,7 %). Les prédicteurs différaient en fonction de chaque type de symptômes. Les symptômes persistants étaient courants chez les personnes âgées (rapport de cotes corrigé [RCc] 1,11, IC à 95 %, 1,04 à 1,18/cinq ans), les personnes diagnostiquées à l'hôpital (RCc 2,03, IC à 95 %, 1,24 à 3,33) et celles dont les manifestations initiales comportaient des symptômes constitutionnels et rhumatologiques. Les patients qui ne répondaient pas au suivi étaient plus jeunes et en meilleure santé au départ. CONCLUSION: Les symptômes persistants sont courants et diversifiés trois mois après la COVID-19, mais sont probablement surestimés dans la plupart des rapports.

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

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

The effects of acute care hospitalization on health and cost trajectories for nursing home residents: A matched cohort study.

Thirty five percent to sixty seven percent of admissions to acute care hospitals from nursing homes are potentially preventable. Limited data exist regarding clinical and cost trajectories post an acute care hospitalization. To describe clinical impact and post-hospitalization costs associated with acute care admissions for nursing home residents. Analysis of population-based data. The 65,996 nursing home residents from a total of 645 nursing homes. Clinical outcomes assessed with the Changes in Health, End-stage disease and Symptoms and Signs (CHESS) scores, and monthly costs. Post-index date, hospitalized residents worsened their clinical conditions, with increases in CHESS scores (CHESS 3 + 24.5% vs 7.6%, SD 0.46), more limitations in activities of daily living (ADL) (86.1% vs 76.0%, SD 0.23), more prescriptions (+1.64 95% CI 1.43-1.86, P < .001), falls (30.9% vs 18.1%, SD 0.16), pressure ulcers (16.4% vs 8.6%, SD 0.37), and bowel incontinence (47.3% vs 39.3%, SD 0.35). Acute care hospitalizations for nursing home residents had a significant impact on their clinical and cost trajectories upon return to the nursing home. Investments in preventive strategies at the nursing home level, and to mitigate functional decline of hospitalized frail elderly residents may lead to improved quality of care and reduced costs for this population. Pre-hospitalization costs were not different between the hospitalized and control groups but showed an immediate increase post-hospitalization (CAD 1882.60 per month, P < .001).

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Behavioral Nudges to Improve Audit and Feedback Report Opening Among Antibiotic Prescribers: A Randomized Controlled Trial.

Background: Peer comparison audit and feedback has demonstrated effectiveness in improving antibiotic prescribing practices, but only a minority of prescribers view their reports. We rigorously tested 3 behavioral nudging techniques delivered by email to improve report opening. Methods: We conducted a pragmatic randomized controlled trial among Ontario long-term care prescribers enrolled in an ongoing peer comparison audit and feedback program which includes data on their antibiotic prescribing patterns. Physicians were randomized to 1 of 8 possible sequences of intervention/control allocation to 3 different behavioral email nudges: a social peer comparison nudge (January 2020), a maintenance of professional certification incentive nudge (October 2020), and a prior participation nudge (January 2021). The primary outcome was feedback report opening; the primary analysis pooled the effects of all 3 nudging interventions. Results: The trial included 421 physicians caring for >28 000 residents at 450 facilities. In the pooled analysis, physicians opened only 29.6% of intervention and 23.9% of control reports (odds ratio [OR], 1.51 [95% confidence interval {CI}, 1.10-2.07], P = .011); this difference remained significant after accounting for physician characteristics and clustering (adjusted OR [aOR], 1.74 [95% CI, 1.24-2.45], P = .0014). Of individual nudging techniques, the prior participation nudge was associated with a significant increase in report opening (OR, 1.62 [95% CI, 1.06-2.47], P = .026; aOR, 2.16 [95% CI, 1.33-3.50], P = .0018). In the pooled analysis, nudges were also associated with accessing more report pages (aOR, 1.28 [95% CI, 1.14-1.43], P < .001). Conclusions: Enhanced nudging strategies modestly improved report opening, but more work is needed to optimize physician engagement with audit and feedback. Clinical Trials Registration: NCT04187742.

Closed loop communication in the trauma bay: identifying opportunities for team performance improvement through a video review analysis.

OBJECTIVES: Communication among trauma team members in the trauma bay is vulnerable to errors, which may impact patient outcomes. We used the previously validated trauma-non-technical skills (T-NOTECHS) tool to identify communication gaps during patient management in the trauma bay and to inform development strategies to improve team performance. METHODS: Two reviewers independently assessed non-technical skills of team members through video footage at Sunnybrook Health Sciences Centre. Team performance was measured using T-NOTECHS across five domains using a five-point Likert scale (lower score indicating worse performance): (1) leadership; (2) cooperation and resource management; (3) communication and interaction; (4) assessment and decision making; (5) situation awareness/coping with stress. Secondary outcomes assessed the number of callouts, closed loop communications and parallel conversations. RESULTS: The study included 55 trauma activations. Injury severity score (ISS) was used as a measure of trauma severity. A case with an ISS score ≥ 16 was considered severe. ISS was ≥ 16 in 37% of cases. Communication and interaction scored significantly lower compared to all other domains (p < 0.0001). There were significantly more callouts and completed closed loop communications in more severe cases compared to less severe cases (p = 0.017 for both). Incomplete closed loop communications and parallel conversations were identified, irrespective of case severity. CONCLUSION: A lower communication score was identified using T-NOTECHS, attributed to incomplete closed loop communications and parallel conversations. Through video review of trauma team activations, opportunities for improvement in communication can be identified by the T-NOTECHS tool, as well as specifically identifying callouts and closed loop communication. This process may be useful for trauma programs as part of a quality improvement program on communication skills and team performance.

RéSUMé: OBJECTIFS : La communication entre les membres de l'équipe de traumatologie dans la salle de traumatologie est vulnérable aux erreurs, ce qui peut avoir un impact sur les résultats des patients. Nous avons utilisé l'outil de compétences non techniques en traumatologie (T-NOTECHS) précédemment validé pour identifier les lacunes en matière de communication pendant la prise en charge des patients dans la salle de traumatologie et pour informer les stratégies de développement visant à améliorer les performances de l'équipe. MéTHODES: Deux examinateurs ont évalué de manière indépendante les compétences non techniques des membres de l'équipe au moyen de séquences vidéo réalisées au Sunnybrook Health Sciences Centre. La performance de l'équipe a été mesurée à l'aide de la T-NOTECHS dans cinq domaines à l'aide d'une échelle de Likert à cinq points (un score plus bas indiquant une performance plus faible) : (1) leadership ; (2) coopération et gestion des ressources ; (3) communication et interaction ; (4) évaluation et prise de décision ; (5) conscience de la situation/ gestion du stress. Les résultats secondaires ont évalué le nombre d'appels, de communications en boucle fermée et de conversations parallèles. RéSULTATS: L'étude a porté sur 55 activations de traumatismes. Le score de gravité des blessures (ISS) a été utilisé comme mesure de la gravité du traumatisme. Un cas présentant un score ISS ≥ 16 était considéré comme grave. L'ISS était ≥ 16 dans 37 % des cas. La communication et l'interaction ont obtenu des scores significativement plus faibles par rapport à tous les autres domaines (p<0,0001). Il y avait significativement plus d'appels et de communications en boucle fermée terminées dans les cas plus graves que dans les cas moins graves (p = 0.017 pour les deux). Des communications incomplètes en boucle fermée et des conversations parallèles ont été identifiées, indépendamment de la gravité du cas. CONCLUSION: Un score de communication plus faible a été identifié en utilisant le T-NOTECHS, attribué à des communications incomplètes en boucle fermée et à des conversations parallèles. Grâce à l'examen vidéo des activations de l'équipe de traumatologie, les possibilités d'amélioration de la communication peuvent être identifiées par l'outil T-NOTECHS, ainsi que l'identification spécifique des appels et de la communication en boucle fermée. Ce processus peut être utile pour les programmes de traumatologie dans le cadre d'un programme d'amélioration de la qualité sur les compétences de communication et la performance de l'équipe.