Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Frailty, Outcomes, Recovery and Care Steps of Critically Ill Patients (FORECAST): a prospective, multi-centre, cohort study.

PURPOSE: Frailty is common in critically ill patients but the timing and optimal method of frailty ascertainment, trajectory and relationship with care processes remain uncertain. We sought to elucidate the trajectory and care processes of frailty in critically ill patients as measured by the Clinical Frailty Scale (CFS) and Frailty Index (FI). METHODS: This is a multi-centre prospective cohort study enrolling patients ≥ 50 years old receiving life support > 24 h. Frailty severity was assessed with a CFS, and a FI based on the elements of a comprehensive geriatric assessment (CGA) at intensive care unit (ICU) admission, hospital discharge and 6 months. For the primary outcome of frailty prevalence, it was a priori dichotomously defined as a CFS ≥ 5 or FI ≥ 0.2. Processes of care, adverse events were collected during ICU and ward stays while outcomes were determined for ICU, hospital, and 6 months. RESULTS: In 687 patients, whose age (mean ± standard deviation) was 68.8 ± 9.2 years, frailty prevalence was higher when measured with the FI (CFS, FI %): ICU admission (29.8, 44.8), hospital discharge (54.6, 67.9), 6 months (34.1, 42.6). Compared to ICU admission, aggregate frailty severity increased to hospital discharge but improved by 6 months; individually, CFS and FI were higher in 45.3% and 50.6% patients, respectively at 6 months. Compared to hospital discharge, 18.7% (CFS) and 20% (FI) were higher at 6 months. Mortality was higher in frail patients. Processes of care and adverse events were similar except for worse ICU/ward mobility and more frequent delirium in frail patients. CONCLUSIONS: Frailty severity was dynamic, can be measured during recovery from critical illness using the CFS and FI which were both associated with worse outcomes. Although the CFS is a global measure, a CGA FI based may have advantages of being able to measure frailty levels, identify deficits, and potential targets for intervention.

Exploring the Impact of Age, Frailty, and Multimorbidity on the Effect of ICU Interventions: A Systematic Review of Randomized Controlled Trials.

OBJECTIVES: To date, age, frailty, and multimorbidity have been used primarily to inform prognosis in older adults. It remains uncertain, however, whether these patient factors may also predict response to critical care interventions or treatment outcomes. DATA SOURCES: We conducted a systematic search of top general medicine and critical care journals for randomized controlled trials (RCTs) examining critical care interventions published between January 1, 2011, and December 31, 2021. STUDY SELECTION: We included RCTs of critical care interventions that examined any one of three subgroups-age, frailty, or multimorbidity. We excluded cluster RCTs, studies that did not report interventions in an ICU, and studies that did not report data examining subgroups of age, frailty, or multimorbidity. DATA EXTRACTION: We collected study characteristics (single vs. multicountry enrollment, single vs. multicenter enrollment, funding, sample size, intervention, comparator, primary outcome and secondary outcomes, length of follow-up), study population (inclusion and exclusion criteria, average age in intervention and comparator groups), and subgroup data. We used the Instrument for assessing the Credibility of Effect Modification Analyses instrument to evaluate the credibility of subgroup findings. DATA SYNTHESIS: Of 2037 unique citations, we included 48 RCTs comprising 50,779 total participants. Seven (14.6%) RCTs found evidence of statistically significant effect modification based on age, whereas none of the multimorbidity or frailty subgroups found evidence of statistically significant subgroup effect. Subgroup credibility ranged from very low to moderate. CONCLUSIONS: Most critical care RCTs do not examine for subgroup effects by frailty or multimorbidity. Although age is more commonly considered, the cut-point is variable, and relative effect modification is rare. Although interventional effects are likely similar across age groups, shared decision-making based on individual patient preferences must remain a priority. RCTs focused specifically on critically ill older adults or those living with frailty and/or multimorbidity are crucial to further address this research question.

A Frailty Index to Predict Mortality, Resource Utilization and Costs in Patients Undergoing Coronary Artery Bypass Graft Surgery in Ontario.

Background: People living with frailty are vulnerable to poor outcomes and incur higher health care costs after coronary artery bypass graft (CABG) surgery. Frailty-defining instruments for population-level research in the CABG setting have not been established. The objectives of the study were to develop a preoperative frailty index for CABG (pFI-C) surgery using Ontario administrative data; assess pFI-C suitability in predicting clinical and economic outcomes; and compare pFI-C predictive capabilities with other indices. Methods: A retrospective cohort study was conducted using health administrative data of 50,682 CABG patients. The pFI-C comprised 27 frailty-related health deficits. Associations between index scores and mortality, resource use and health care costs (2022 Canadian dollars [CAD]) were assessed using multivariable regression models. Capabilities of the pFI-C in predicting mortality were evaluated using concordance statistics; goodness of fit of the models was assessed using Akakie Information Criterion. Results: As assessed by the pFI-C, 22% of the cohort lived with frailty. The pFI-C score was strongly associated with mortality per 10% increase (odds ratio [OR], 3.04; 95% confidence interval [CI], [2.83,3.27]), and was significantly associated with resource utilization and costs. The predictive performances of the pFI-C, Charlson, and Elixhauser indices and Johns Hopkins Aggregated Diagnostic Groups were similar, and mortality models containing the pFI-C had a concordance (C)-statistic of 0.784. Cost models containing the pFI-C showed the best fit. Conclusions: The pFI-C is predictive of mortality and associated with resource utilization and costs during the year following CABG. This index could aid in identifying a subgroup of high-risk CABG patients who could benefit from targeted perioperative health care interventions.

Contexte: Les personnes dont l'état de santé est fragilisé sont susceptibles de connaître des issues défavorables et de générer des coûts plus élevés pour le système de santé après un pontage aortocoronarien. Aucun instrument n'a été établi pour définir la fragilité dans la recherche populationnelle en contexte de pontage aortocoronarien. Les objectifs de l'étude étaient les suivants : 1) concevoir un indice de fragilité préopératoire en vue d'un pontage aortocoronarien (preoperative frailty index for CABG surgery, pFI-C) en utilisant des données administratives de l'Ontario; 2) évaluer la capacité de cet indice à prédire les issues cliniques et économiques; et 3) comparer la valeur prédictive de cet indice avec celle d'autres indices. Méthodologie: Une étude de cohorte rétrospective a été menée à partir de données médico-administratives portant sur 50 682 patients ayant subi un pontage aortocoronarien. Le pFI-C comprenait 27 déficits de santé liés à la fragilité. Des liens entre les scores de l'indice et la mortalité, l'utilisation des ressources et les coûts de soins de santé (en $ CA de 2022) ont été évalués à l'aide de modèles de régression multivariable. La capacité du pFI-C à prédire la mortalité a été évaluée à l'aide de la statistique de concordance; la qualité de l'ajustement des modèles a été évaluée en fonction du critère d'information d'Akaike. Résultats: Selon l'évaluation par le pFI-C, 22 % de la cohorte vivait avec une fragilité. Le score de l'indice était fortement corrélé à la mortalité par tranche d'augmentation de 10 % (rapport de cotes de 3,04; intervalle de confiance à 95 % de 2,83 à 3,27) et était corrélé de manière significative à l'utilisation des ressources et aux coûts. La valeur prédictive du pFI-C, des indices de Charlson et Elixhauser, et de Johns Hopkins Aggregated Diagnostic Groups était similaire, et les modèles de mortalité contenant le pFI-C affichaient une valeur statistique C de 0,784. Les modèles de coûts contenant le pFI-C affichaient le meilleur ajustement. Conclusions: Le pFI-C est un facteur prédictif de mortalité et est corrélé à l'utilisation des ressources et aux coûts engagés durant l'année qui suit un pontage aortocoronarien. Cet indice pourrait faciliter la détection d'un sous-groupe de patients subissant un pontage aortocoronarien et présentant un risque élevé qui pourraient bénéficier de soins périopératoires ciblés.

Patient-important upper gastrointestinal bleeding in the ICU: A mixed-methods study of patient and family perspectives.

INTRODUCTION: The objective of this study was to create a definition of patient-important upper gastrointestinal bleeding during critical illness as an outcome for a randomized trial. DESIGN: This was a sequential mixed-methods qualitative-dominant multi-center study with an instrument-building aim. In semi-structured individual interviews or focus groups we elicited views from survivors of critical illness and family members of patients in the intensive care unit (ICU) regarding which features indicate important gastrointestinal bleeding. Quantitative demographic characteristics were collected. We analyzed qualitative data using inductive content analysis to develop a definition for patient-important upper gastrointestinal bleeding. SETTING: Canada and the United States. PARTICIPANTS: 51 ICU survivors and family members of ICU patients. RESULTS: Participants considered gastrointestinal bleeding to be important if it resulted in death, disability, or prolonged hospitalization. The following also signaled patient-important upper gastrointestinal bleeding: blood transfusion, vasopressors, endoscopy, CT-angiography, or surgery. Whether an intervention evinced concern depended on its effectiveness, side-effects, invasiveness and accessibility; contextual influences included participant familiarity and knowledge of interventions and trust in the clinical team. CONCLUSIONS: Survivors of critical illness and family members described patient-important upper gastrointestinal bleeding differently than current definitions of clinically-important upper gastrointestinal bleeding.

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study.

OBJECTIVES: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Multicenter ICU study. PATIENTS: Adults requiring invasive mechanical ventilation secondary to COVID-19. INTERVENTION: Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao2/Fio2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events. CONCLUSIONS: In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao2/Fio2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.

The inaugural Canadian Conferences on Translational Geroscience were held as two complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This manuscript summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada.

Ceragenin-coated endotracheal tubes for the reduction of ventilator-associated pneumonia: a prospective, longitudinal, cross-over, interrupted time, implementation study protocol (CEASE VAP study).

BACKGROUND: Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes. METHODS: In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay. ETHICS AND DISSEMINATION: This study has been approved by the Health Sciences Research Ethics Board at Queen's University. The results of this study will be actively disseminated through manuscript publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT05761613.

Cerebral autoregulation-based mean arterial pressure targets and delirium in critically ill adults without brain injury: a retrospective cohort study.

PURPOSE: Cerebral autoregulation (CA) is a mechanism that acts to maintain consistent cerebral perfusion across a range of blood pressures, and impaired CA is associated with delirium. Individualized CA-derived blood pressure targets are poorly characterized in critically ill patients and the association with intensive care unit (ICU) delirium is unknown. Our objectives were to characterize optimal mean arterial pressure (MAPopt) ranges in critically ill adults without brain injury and determine whether deviations from these targets contribute to ICU delirium. METHODS: We performed a retrospective cohort analysis of patients with shock of any etiology and/or respiratory failure requiring invasive mechanical ventilation, without a neurologic admitting diagnosis. Patients were screened daily for delirium. Cerebral oximetry and mean arterial pressure data were captured for the first 24 hr from enrolment. RESULTS: Forty-two patients with invasive blood pressure monitoring data were analyzed. Optimal mean arterial pressure targets ranged from 55 to 100 mm Hg. Optimal mean arterial pressure values were not significantly different based on history of hypertension or delirium status, and delirium was not associated with deviations from MAPopt. Nevertheless, the majority (69%) of blood pressure targets exceeded the current 65 mm Hg Surviving Sepsis guidelines. CONCLUSION: We observed that MAPopt targets across patients were highly variable, but did not observe an association with the incidence of delirium. Studies designed to evaluate the impact on neurologic outcomes are needed to understand the association with individualized mean arterial pressure targets in the ICU. STUDY REGISTRATION: ClinicalTrials.gov (NCT02344043); first submitted 22 January 2015.

RéSUMé: OBJECTIF: L'autorégulation cérébrale (AC) est un mécanisme qui agit pour maintenir une perfusion cérébrale constante pour une gamme de tensions artérielles, et une altération de l'AC est associée au delirium. Les cibles de tension artérielle individualisées dérivées de l'AC sont mal caractérisées chez les patient·es gravement malades et l'association avec le delirium à l'unité de soins intensifs (USI) est inconnue. Nos objectifs étaient de caractériser la tension artérielle moyenne optimale (TAMopt) chez les adultes gravement malades sans lésion cérébrale et de déterminer si les écarts par rapport à ces cibles contribuaient au delirium à l'USI. MéTHODE: Nous avons réalisé une analyse de cohorte rétrospective de patient·es présentant un choc de toute étiologie et/ou une insuffisance respiratoire nécessitant une ventilation mécanique invasive, et n'ayant pas reçu de diagnostic d'atteinte neurologique à l'admission. Les patients ont été dépistés quotidiennement pour le delirium. Les données d'oxymétrie cérébrale et de tension artérielle moyenne ont été saisies pendant les 24 premières heures suivant le recrutement. RéSULTATS: Quarante-deux patient·es pour qui des données de monitorage invasif de la tension artérielle étaient disponibles ont été analysé·es. Les cibles optimales de tension artérielle moyenne variaient de 55 à 100 mm Hg. Les valeurs optimales de tension artérielle moyenne n'étaient pas significativement différentes en fonction des antécédents d'hypertension ou de delirium, et le delirium n'était pas associé à des écarts par rapport à la TAMopt. Néanmoins, la majorité (69 %) des cibles de tension artérielle dépassaient celle de 65 mm Hg préconisée par les lignes directrices Surviving Sepsis. CONCLUSION: Nous avons observé que les cibles de TAMopt étaient très variables chez les patient·es, mais nous n'avons pas observé d'association avec l'incidence de delirium. Des études conçues pour évaluer l'impact sur les issues neurologiques sont nécessaires pour comprendre l'association avec les cibles de tension artérielle moyenne individualisées à l'USI. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02344043); soumis pour la première fois le 22 janvier 2015.

REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial.

BACKGROUND: The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. OBJECTIVE: To outline the statistical analysis plan for the REVISE trial. METHODS: REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. RESULTS: The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are 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 concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. CONCLUSIONS: This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT03374800. November 21, 2017.

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

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.

Nebulised furosemide for the treatment of patients with obstructive lung disease: a systematic review protocol.

INTRODUCTION: Obstructive lung diseases (OLDs) such as asthma and chronic obstructive pulmonary disease are major global sources of morbidity and mortality. Current treatments broadly include bronchodilators such as beta agonists/antimuscarinics and anti-inflammatory agents such as steroids. Despite therapy patients still experience exacerbations of their diseases and overall decline over time. Nebulised furosemide may have a novel use in the treatment of OLD. Multiple small studies have shown improvement in pulmonary function as well as dyspnoea. This systematic review will aim to summarise and analyse the existing literature on nebulised furosemide use in OLD to guide treatment and future studies. METHODS AND ANALYSIS: We will identify all experimental studies using nebulised/inhaled furosemide in patients with asthma or chronic obstructive pulmonary disease that report any outcome. Databases will include EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and the NHS Economic Evaluation Database (1995-2015). We will also search ClinicalTrials.gov and the WHO-International Clinical Trials Registry Platform. Two reviewers will independently determine trial eligibility. For each included trial, we will perform duplicate independent data extraction, risk of bias assessment and evaluation of the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: Ethical approval will not be applicable to this systematic review. The results of the study will be communicated through publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021284680.

Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial.

BACKGROUND: Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection. METHODS: The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection. DISCUSSION: Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research. TRIAL REGISTRATION: REVISE Trial [NCT03374800 December 15, 2017], COVID-19 Cohort Study [NCT05715567 February 8, 2023].

Neurological Impairment in Critically Ill Patients on Dialysis: Research Letter for the INCOGNITO-AKI Feasibility Study.

Background: Acute kidney injury (AKI) resulting in kidney replacement therapy is rising among critically ill adults. Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation (rSO2) may be a contributing factor. Objective: To assess the feasibility of testing the association between intradialytic rSO2 and acute and long-term neurological outcomes. Design: Longitudinal observational study. Setting and Participants: We enrolled patients initiating continuous kidney replacement therapy or intermittent hemodialysis in the Kingston Health Sciences Centre (KHSC) Intensive Care Unit (ICU). Measurements and Methods: rSO2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging. Results: Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSO2/vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors. Limitations: Enrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes. Conclusion: rSO2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up.

Contexte: L'insuffisance rénale aiguë (IRA) menant à une thérapie de remplacement rénal est en augmentation chez les adultes aux soins intensifs. Un séjour aux soins intensifs et la thérapie de remplacement rénal à long terme sont indépendamment liés à des déficits cognitifs aigus et prolongés ainsi qu'à des pathologies structurelles du cerveau. La faible saturation régionale du cerveau en oxygène (rSO2) pourrait être un facteur contributif. Objectif: Évaluer la possibilité de tester l'association entre la rSO2 intradialytique et les résultats neurologiques aigus et chroniques. Type d'étude: Étude observationnelle longitudinale. Cadre et sujets de l'étude: Nous avons recruté des patients qui entamaient une thérapie de remplacement rénal en continu ou une hémodialyse intermittente à l'unité des soins intensifs (USI) du Kingston Health Sciences Centre (KHSC). Mesures et méthodologie: La rSO2 a été surveillée pendant les 72 premières heures de thérapie de remplacement rénal en continu, ou tout au long de chaque séance d'hémodialyse intermittente. Nous avons mesuré les déficits neurologiques aigus par un dépistage quotidien du délirium et les atteintes neurocognitives à long terme à l'aide du robot Kinarm, de la Repeatable Battery for the Assessment of Neuropsychological Status et de l'imagerie par résonance magnétique cérébrale. Résultats: Sur les 484 patients hospitalisés à l'USI, 26 répondaient aux critères de sélection. Deux ont refusé de participer à l'étude et treize satisfaisaient à au moins un critère d'exclusion. Onze patients ont été inclus à l'étude. Huit patients sont décédés à l'USI, un est décédé deux mois après sa sortie de l'hôpital et un a refusé le suivi. Les taux de saisie des données étaient élevés: rSO2 et paramètres vitaux (91,3 %), dépistage du délirium et démographie (100 %). Des tests longitudinaux ont été effectués chez 50 % (1 de 2) des survivants. Limites: Le taux d'inscription était faible en raison de divers facteurs, ce qui a limité notre capacité à évaluer les résultats à long terme. Conclusion: Il est possible de collecter des données sur la rSO2 et le délirium chez les patients de soins intensifs qui suivent une thérapie de remplacement rénal; un taux de mortalité élevé a limité le suivi. Trial Registration: clinicaltrials.gov, registration number NCT04722939.

Critical Care Cycling to Improve Lower Extremity Strength (CYCLE): protocol for an international, multicentre randomised clinical trial of early in-bed cycling for mechanically ventilated patients.

INTRODUCTION: In-bed leg cycling with critically ill patients is a promising intervention aimed at minimising immobility, thus improving physical function following intensive care unit (ICU) discharge. We previously completed a pilot randomised controlled trial (RCT) which supported the feasibility of a large RCT. In this report, we describe the protocol for an international, multicentre RCT to determine the effectiveness of early in-bed cycling versus routine physiotherapy (PT) in critically ill, mechanically ventilated adults. METHODS AND ANALYSIS: We report a parallel group RCT of 360 patients in 17 medical-surgical ICUs and three countries. We include adults (≥18 years old), who could ambulate independently before their critical illness (with or without a gait aid), ≤4 days of invasive mechanical ventilation and ≤7 days ICU length of stay, and an expected additional 2-day ICU stay, and who do not fulfil any of the exclusion criteria. After obtaining informed consent, patients are randomised using a web-based, centralised system to either 30 min of in-bed cycling in addition to routine PT, 5 days per week, up to 28 days maximum, or routine PT alone. The primary outcome is the Physical Function ICU Test-scored (PFIT-s) at 3 days post-ICU discharge measured by assessors blinded to treatment allocation. Participants, ICU clinicians and research coordinators are not blinded to group assignment. Our sample size estimate was based on the identification of a 1-point mean difference in PFIT-s between groups. ETHICS AND DISSEMINATION: Critical Care Cycling to improve Lower Extremity (CYCLE) is approved by the Research Ethics Boards of all participating centres and Clinical Trials Ontario (Project 1345). We will disseminate trial results through publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot).

Effectiveness of interventions to address different types of vulnerabilities in community-dwelling older adults: An umbrella review.

Background: Frailty, social isolation, loneliness, and poverty may render older adults vulnerable to social or health stressors. It is imperative to identify effective interventions to address them especially in the context of COVID-19 pandemic. Objective: To identify effective community-based interventions to address frailty, social isolation, loneliness, and poverty among community-dwelling older adults. Design: Umbrella review. Data Source: We systematically searched PubMed, Ovid MEDLINE, Embase, Cochrane CENTRAL, EBM-Reviews, CINAHL via EBSCO, and APA PsycInfo via Ovid from January 2009 to December 2022. Eligibility Criteria: We included systematic reviews or quantitative reviews of non-pharmacologic interventions targeting community-dwelling older adults. Data Selection Extraction and Management: Two review authors independently screened the titles and abstracts, performed data extraction and appraised the methodological quality of the reviews. We used a narrative synthesis approach to summarize and interpret the findings. We assessed the methodological quality of the studies using AMSTAR 2.0 tool. Results: We identified 27 reviews incorporating 372 unique primary studies that met our inclusion criteria. Ten of the reviews included studies conducted in low-middle-income countries. Twelve reviews (46%, 12/26) included interventions that addressed frailty. Seventeen reviews (65%, 17/26) included interventions that addressed either social isolation or loneliness. Eighteen reviews included studies with single component interventions, while 23 reviews included studies with multi-component interventions. Interventions including protein supplementation combined with physical activity may improve outcomes including frailty status, grip strength, and body weight. Physical activity alone or in combination with diet may prevent frailty. Additionally, physical activity may improve social functioning and interventions using digital technologies may decrease social isolation and loneliness. We did not find any review of interventions addressing poverty among older adults. We also noted that few reviews addressed multiple vulnerabilities within the same study, specifically addressed vulnerability among ethnic and sexual minority groups, or examined interventions that engaged communities and adapted programs to local needs. Conclusion: Evidence from reviews support diets, physical activity, and digital technologies to improve frailty, social isolation or loneliness. However, interventions examined were primarily conducted under optimal conditions. There is a need for further interventions in community settings and conducted under real world settings in older adults living with multiple vulnerabilities.

What counts as patient-important upper gastrointestinal bleeding in the ICU? A mixed-methods study protocol of patient and family perspectives.

INTRODUCTION: Clinically important upper gastrointestinal bleeding is conventionally defined as bleeding accompanied by haemodynamic changes, requiring red blood cell transfusions or other invasive interventions. However, it is unclear if this clinical definition reflects patient values and preferences. This protocol describes a study to elicit views from patients and families regarding features, tests, and treatments for upper gastrointestinal bleeding that are important to them. METHODS AND ANALYSIS: This is a sequential mixed-methods qualitative-dominant multi-centre study with an instrument-building aim. We developed orientation tools and educational materials in partnership with patients and family members, including a slide deck and executive summary. We will invite intensive care unit (ICU) survivors and family members of former ICU patients to participate. Following a virtual interactive presentation, participants will share their perspectives in an interview or focus group. Qualitative data will be analysed using inductive qualitative content analysis, wherein codes will be derived directly from the data rather than using preconceived categories. Concurrent data collection and analysis will occur. Quantitative data will include self-reported demographic characteristics. This study will synthesise the values and perspectives of patients and family members to create a new trial outcome for a randomised trial of stress ulcer prophylaxis. This study is planned for May 2022 to August 2023. The pilot work was completed in Spring 2021. ETHICS AND DISSEMINATION: This study has ethics approval from McMaster University and the University of Calgary. Findings will be disseminated via manuscript and through incorporation as a secondary trial outcome on stress ulcer prophylaxis. TRIAL REGISTRATION NUMBER: NCT05506150.