Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

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.

Scale-up and sustainability of a personalized end-of-life care intervention: a longitudinal mixed-methods study.

BACKGROUND: Scaling-up and sustaining healthcare interventions can be challenging. Our objective was to describe how the 3 Wishes Project (3WP), a personalized end-of-life intervention, was scaled-up and sustained in an intensive care unit (ICU). METHODS: In a longitudinal mixed-methods study from January 12,013 - December 31, 2018, dying patients and families were invited to participate if the probability of patient death was > 95% or after a decision to withdraw life support. A research team member or bedside clinician learned more about each of the patients and their family, then elicited and implemented at least 3 personalized wishes for patients and/or family members. We used a qualitative descriptive approach to analyze interviews and focus groups conducted with 25 clinicians who cared for the enrolled patients. We used descriptive statistics to summarize patient, wish, and clinician characteristics, and analyzed outcome data in quarters using Statistical Process Control charts. The primary outcome was enrollment of terminally ill patients and respective families; the secondary outcome was the number of wishes per patient; tertiary outcomes included wish features and stakeholder involvement. RESULTS: Both qualitative and quantitative analyses suggested a three-phase approach to the scale-up of this intervention during which 369 dying patients were enrolled, having 2039 terminal wishes implemented. From a research project to clinical program to an approach to practice, we documented a three-fold increase in enrolment with a five-fold increase in total wishes implemented, without a change in cost. Beginning as a study, the protocol provided structure; starting gradually enabled frontline staff to experience and recognize the value of acts of compassion for patients, families, and clinicians. The transition to a clinical program was marked by handover from the research staff to bedside staff, whereby project catalysts mentored project champions to create staff partnerships, and family engagement became more intentional. The final transition involved empowering staff to integrate the program as an approach to care, expanding it within and beyond the organization. CONCLUSIONS: The 3WP is an end-of-life intervention which was implemented as a study, scaled-up into a clinical program, and sustained by becoming integrated into practice as an approach to care.

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.

Principles Guiding Nonpandemic Critical Care Research During a Pandemic.

OBJECTIVES: To describe the importance of critical care clinical research that is not pandemic-focused during pandemic times; outline principles to assist in the prioritization of nonpandemic research during pandemic times; and propose a guiding framework for decisions about whether, when and how to continue nonpandemic research while still honoring the moral and scientific imperative to launch research that is pandemic-focused. DESIGN/DATA SOURCES: Using in-person, email, and videoconference exchanges, we convened an interprofessional clinical research group, conducted a literature review of empirical studies, ethics documents and expert commentaries (2010 to present), and viewed traditional and social media posts (March 2020 to May 2020). Stakeholder consultation involved scientific, ethics, clinical, and administrative leaders. SETTING: Clinical research in the ICU. PATIENTS: Patients with and without coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: While clinical research should be prioritized to advantage patients with coronavirus disease 2019 in order to care for affected patients, it ideally would not unduly disadvantage patients without coronavirus disease 2019. Thus, timely, rigorous, relevant, and ethical clinical research is needed to improve the care and optimize outcomes for both patients with and without coronavirus disease 2019, acknowledging how many studies that are not exclusively focused on coronavirus disease 2019 remain relevant to patients with coronavirus disease 2019. Considerations to continue nonpandemic-focused research include the status of the pandemic, local jurisdictional guidance, capacity and safety of bedside and research personnel, disposition of patients already enrolled in nonpandemic studies, analyzing characteristics of each nonpandemic-focused study, research oversight, and final reporting requirements. CONCLUSIONS: Deliberation about continuing nonpandemic research should use objective, transparent criteria considering several aspects of the research process such as bedside and research staff safety, infection control, the informed consent model, protocol complexity, data collection, and implementation integrity. Decisions to pause or pursue nonpandemic research should be proportionate, transparent, and revisited as the pandemic abates.

Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study.

BACKGROUND: Host-associated microbial communities have important roles in tissue homeostasis and overall health. Severe perturbations can occur within these microbial communities during critical illness due to underlying diseases and clinical interventions, potentially influencing patient outcomes. We sought to profile the microbial composition of critically ill mechanically ventilated patients, and to determine whether microbial diversity is associated with illness severity and mortality. METHODS: We conducted a prospective, observational study of mechanically ventilated critically ill patients with a high incidence of pneumonia in 2 intensive care units (ICUs) in Hamilton, Canada, nested within a randomized trial for the prevention of healthcare-associated infections. The microbial profiles of specimens from 3 anatomical sites (respiratory, and upper and lower gastrointestinal tracts) were characterized using 16S ribosomal RNA gene sequencing. RESULTS: We collected 65 specimens from 34 ICU patients enrolled in the trial (29 endotracheal aspirates, 26 gastric aspirates and 10 stool specimens). Specimens were collected at a median time of 3 days (lower respiratory tract and gastric aspirates; interquartile range [IQR] 2-4) and 6 days (stool; IQR 4.25-6.75) following ICU admission. We observed a loss of biogeographical distinction between the lower respiratory tract and gastrointestinal tract microbiota during critical illness. Moreover, microbial diversity in the respiratory tract was inversely correlated with APACHE II score (r = - 0.46, p = 0.013) and was associated with hospital mortality (Median Shannon index: Discharged alive; 1.964 vs. Deceased; 1.348, p = 0.045). CONCLUSIONS: The composition of the host-associated microbial communities is severely perturbed during critical illness. Reduced microbial diversity reflects high illness severity and is associated with mortality. Microbial diversity may be a biomarker of prognostic value in mechanically ventilated patients. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01782755 . Registered February 4 2013.

Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis.

INTRODUCTION: A decreased frequency of upper gastrointestinal bleeding and a possible association of proton pump inhibitor use with Clostridium difficile and ventilator-associated pneumonia have raised concerns recently. The Reevaluating the Inhibition of Stress Erosions Pilot Trial determined the feasibility of undertaking a larger trial investigating the efficacy and safety of withholding proton pump inhibitors in critically ill patients. METHODS: In 10 ICUs, we randomized adult ICU patients anticipated to be mechanically ventilated for greater than or equal to 48 hours to receive 40 mg of IV pantoprazole daily or placebo. We excluded patients who had acute or recent gastrointestinal bleed, used dual antiplatelet agents, had a medical condition requiring proton pump inhibitor treatment, or had already received more than one dose of acid suppression daily. Patients, families, clinicians, and research staff were blinded. We conducted a systematic review and meta-analysis of similar trials. MAIN RESULTS: Ninety-one patients (49 pantoprazole and 42 placebo) from 10 centers in Canada, Saudi Arabia, and Australia were enrolled. All feasibility goals were met: 1) recruitment rate was 2.6 patients per month; 2) consent rate was 77.8%; and 3) protocol adherence was 97.7%. Upper gastrointestinal bleeding developed in 6.1% of patients in the pantoprazole group and 4.8% in the placebo group (p = 1.0). Ventilator-associated pneumonia developed in 20.4% of patients in the pantoprazole group and 14.3% in the placebo group (p = 0.58). C. difficile was identified in 4.1% pantoprazole patients and in 2.4% placebo patients (p = 1.0). We meta-analyzed five trials (604 patients) of proton pump inhibitors versus placebo; there was no statistically significant difference in the risk of upper gastrointestinal bleeding, infections, or mortality. CONCLUSIONS: Our results support the feasibility of a larger trial to evaluate the safety of withholding stress ulcer prophylaxis. Although the results are imprecise, there was no alarming increase in the risk of upper gastrointestinal bleeding; the effect of proton pump inhibitors on ventilator-associated pneumonia and C. difficile remain unclear.

Personalizing death in the intensive care unit: the 3 Wishes Project: a mixed-methods study.

BACKGROUND: Dying in the complex, efficiency-driven environment of the intensive care unit can be dehumanizing for the patient and have profound, long-lasting consequences for all persons attendant to that death. OBJECTIVE: To bring peace to the final days of a patient's life and to ease the grieving process. DESIGN: Mixed-methods study. SETTING: 21-bed medical-surgical intensive care unit. PARTICIPANTS: Dying patients and their families and clinicians. INTERVENTION: To honor each patient, a set of wishes was generated by patients, family members, or clinicians. The wishes were implemented before or after death by patients, families, clinicians (6 of whom were project team members), or the project team. MEASUREMENTS: Quantitative data included demographic characteristics, processes of care, and scores on the Quality of End-of-Life Care-10 instrument. Semistructured interviews of family members and clinicians were transcribed verbatim, and qualitative description was used to analyze them. RESULTS: Participants included 40 decedents, at least 1 family member per patient, and 3 clinicians per patient. The 159 wishes were implemented and classified into 5 categories: humanizing the environment, tributes, family reconnections, observances, and "paying it forward." Scores on the Quality of End-of-Life Care-10 instrument were high. The central theme from 160 interviews of 170 persons was how the 3 Wishes Project personalized the dying process. For patients, eliciting and customizing the wishes honored them by celebrating their lives and dignifying their deaths. For families, it created positive memories and individualized end-of-life care for their loved ones. For clinicians, it promoted interprofessional care and humanism in practice. LIMITATION: Impaired consciousness limited understanding of patients' viewpoints. CONCLUSION: The 3 Wishes Project facilitated personalization of the dying process through explicit integration of palliative and spiritual care into critical care practice. PRIMARY FUNDING SOURCE: Hamilton Academy of Health Science Research Organization, Canadian Intensive Care Foundation.

Dalteparin versus unfractionated heparin in critically ill patients.

BACKGROUND: The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients. METHODS: In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle. RESULTS: There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046). CONCLUSIONS: Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

Thromboprophylaxis patterns and determinants in critically ill patients: a multicenter audit.

INTRODUCTION: Heparin is safe and prevents venous thromboembolism in critical illness. We aimed to determine the guideline concordance for thromboprophylaxis in critically ill patients and its predictors, and to analyze factors associated with the use of low molecular weight heparin (LMWH), as it may be associated with a lower risk of pulmonary embolism and heparin-induced thrombocytopenia without increasing the bleeding risk. METHODS: We performed a retrospective audit in 28 North American intensive care units (ICUs), including all consecutive medical-surgical patients admitted in November 2011. We documented ICU thromboprophylaxis and reasons for omission. Guideline concordance was determined by adding days in which patients without contraindications received thromboprophylaxis to days in which patients with contraindications did not receive it, divided by the total number of patient-days. We used multilevel logistic regression including time-varying, center and patient-level covariates to determine the predictors of guideline concordance and use of LMWH. RESULTS: We enrolled 1,935 patients (62.3 ± 16.7 years, Acute Physiology and Chronic Health Evaluation [APACHE] II score 19.1 ± 8.3). Patients received thromboprophylaxis with unfractionated heparin (UFH) (54.0%) or LMWH (27.6%). Guideline concordance occurred for 95.5% patient-days and was more likely in patients who were sicker (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.17, 1.75 per 10-point increase in APACHE II), heavier (OR 1.32, 95% CI 1.05, 1.65 per 10-m/kg2 increase in body mass index), had cancer (OR 3.22, 95% CI 1.81, 5.72), previous venous thromboembolism (OR 3.94, 95% CI 1.46,10.66), and received mechanical ventilation (OR 1.83, 95% CI 1.32,2.52). Reasons for not receiving thromboprophylaxis were high risk of bleeding (44.5%), current bleeding (16.3%), no reason (12.9%), recent or upcoming invasive procedure (10.2%), nighttime admission or discharge (9.7%), and life-support limitation (6.9%). LMWH was less often administered to sicker patients (OR 0.65, 95% CI 0.48, 0.89 per 10-point increase in APACHE II), surgical patients (OR 0.41, 95% CI 0.24, 0.72), those receiving vasoactive drugs (OR 0.47, 95% CI 0.35, 0.64) or renal replacement therapy (OR 0.10, 95% CI 0.05, 0.23). CONCLUSIONS: Guideline concordance for thromboprophylaxis was high, but LMWH was less commonly used, especially in patients who were sicker, had surgery, or received vasopressors or renal replacement therapy, representing a potential quality improvement target.

Adjudication of a primary trial outcome: Results of a calibration exercise and protocol for a large international trial.

Background: Ascertainment of the severity of the primary outcome of upper gastrointestinal (GI) bleeding is integral to stress ulcer prophylaxis trials. This protocol outlines the adjudication process for GI bleeding events in an international trial comparing pantoprazole to placebo in critically ill patients (REVISE: Re-Evaluating the Inhibition of Stress Erosions). The primary objective of the adjudication process is to assess episodes submitted by participating sites to determine which fulfil the definition of the primary efficacy outcome of clinically important upper GI bleeding. Secondary objectives are to categorize the bleeding severity if deemed not clinically important, and adjudicate the bleeding site, timing, investigations, and treatments. Methods: Research coordinators follow patients daily for any suspected clinically important upper GI bleeding, and submit case report forms, doctors' and nurses' notes, laboratory, imaging, and procedural reports to the methods center. An international central adjudication committee reflecting diverse specialty backgrounds conducted an initial calibration exercise to delineate the scope of the adjudication process, review components of the definition, and agree on how each criterion will be considered fulfilled. Henceforth, bleeding events will be stratified by study drug, and randomly assigned to adjudicator pairs (blinded to treatment allocation, and study center). Results: Crude agreement, chance-corrected agreement, or chance-independent agreement if data have a skewed distribution will be calculated. Conclusions: Focusing on consistency and accuracy, central independent blinded duplicate adjudication of suspected clinically important upper GI bleeding events will determine which events fulfil the definition of the primary efficacy outcome for this stress ulcer prophylaxis trial. Registration: NCT03374800 (REVISE: Re-Evaluating the Inhibition of Stress Erosions).

Barriers, Solutions, and Opportunities for Adapting Critical Care Clinical Trials in the COVID-19 Pandemic.

Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation. Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials. Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024. Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking. Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence. Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.

Co-enrollment of critically ill patients into multiple studies: patterns, predictors and consequences.

INTRODUCTION: Research on co-enrollment practices and their impact are limited in the ICU setting. The objectives of this study were: 1) to describe patterns and predictors of co-enrollment of patients in a thromboprophylaxis trial, and 2) to examine the consequences of co-enrollment on clinical and trial outcomes. METHODS: In an observational analysis of an international thromboprophylaxis trial in 67 ICUs, we examined the co-enrollment of critically ill medical-surgical patients into more than one study, and examined the clinical and trial outcomes among co-enrolled and non-co-enrolled patients. RESULTS: Among 3,746 patients enrolled in PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial), 713 (19.0%) were co-enrolled in at least one other study (53.6% in a randomized trial, 37.0% in an observational study and 9.4% in both). Six factors independently associated with co-enrollment (all P < 0.001) were illness severity (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.19 to 1.53 for each 10-point Acute Physiology and Chronic Health Evaluation (APACHE) II score increase), substitute decision-makers providing consent, rather than patients (OR 3.31, 2.03 to 5.41), experience of persons inviting consent (OR 2.67, 1.74 to 4.11 for persons with > 10 years' experience compared to persons with none), center size (all ORs > 10 for ICUs with > 15 beds), affiliation with trials groups (OR 5.59, 3.49 to 8.95), and main trial rather than pilot phase (all ORs > 8 for recruitment year beyond the pilot). Co-enrollment did not influence clinical or trial outcomes or risk of adverse events. CONCLUSIONS: Co-enrollment was strongly associated with features of the patients, research personnel, setting and study. Co-enrollment had no impact on trial results, and appeared safe, acceptable and feasible. Transparent reporting, scholarly discourse, ethical analysis and further research are needed on the complex topic of co-enrollment during critical illness.

International variation in ethics and contract approval processes for a low-risk observational study of mechanical ventilation discontinuation practices.

OBJECTIVES: To describe international variation in ethics and contract processes, identify predictors of approval times, and reasons for nonparticipation in an international observational study of ventilation discontinuation practices. STUDY DESIGN AND SETTING: A nested cross-sectional survey of research personnel at 111 participating sites (representing 142 intensive care units [ICUs]) from six geographic regions (Canada, India, the United Kingdom, Europe, Australia/New Zealand, and the United States). RESULTS: We analyzed responses from 80 sites (72.1% response rate). A single local or central approval was required at 34/80 (42.5%) and 23/80 (28.75%), respectively. Of those requiring central ethics approval, 20/23 (87.0%) sites required an additional approval. Sites with central vs. other ethics approval processes had significantly longer times to ethics approval (176 vs. 42 days; P < 0.0001). The median time to contract execution was 140 days (range: 11-1,215) with sites in India and the United States having the shortest and longest times to contract execution, respectively. We did not identify independent predictors of approval times. Of 190 sites that initially agreed to participate, 78 (41%) sites (89 ICUs) were ultimately unable to participate. CONCLUSION: International ethics and contract approval times were lengthy and highly variable. Central ethics review processes significantly increased approval times.

Clostridioides difficile infection in mechanically ventilated critically ill patients: A nested cohort study.

INTRODUCTION: Clostridioides difficile infection (CDI) is a serious complication of critical illness. The objective of the study was to determine its incidence, prevalence, timing, severity, predictors, and outcomes. METHODS: We performed a prospective nested cohort study of CDI within a randomized trial comparing Lactobacillus rhamnosus GG to placebo. We adjudicated cases of CDI using standardized definitions, assessed timing (pre-ICU, in ICU, post-ICU) and severity. We analyzed risk factors and outcomes. RESULTS: Of 2650 patients, 86 were diagnosed with CDI during 90,833 hospital-days (0.95/1000 hospital-days); CDI prevalence was 3.2%. CDI incidence varied in timing; 0.3% patients had CDI pre-ICU, 2.2% in the ICU; an 0.8% developed CDI post-ICU. Relapse or recurrence of CDI was documented in 9.3% patients. Infections were mild/moderate in severity. Complications included septic shock (26.7%), organ failure (16.3%), and toxic megacolon requiring colectomy (1.2%). No risk factors for CDI were identified. CDI was not associated with hospital mortality. The duration of hospital stay was longer for those who had CDI compared those who did not, CONCLUSION: CDI was uncommon, severity was mild to moderate and not associated with mortality however CDI was associated with a longer hospital stay.

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].

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.

Definitions, rates and associated mortality of ICU-acquired pneumonia: A multicenter cohort study.

INTRODUCTION: We aimed to analyze intensive care unit (ICU)-acquired pneumonia according to 7 definitions, estimating associated hospital mortality. METHODS: This cohort study was nested within an international randomized trial, evaluating the effect of probiotics on ICU-acquired pneumonia in 2650 mechanically ventilated adults. Each clinically suspected pneumonia was adjudicated by two physicians blinded to allocation and center. The primary outcome was ventilator-associated pneumonia (VAP) informed by ventilation for ≥2 days, new, progressive or persistent infiltrate plus 2 of: temperature > 38 °C or < 36 °C; leukopenia (<3 × 10(Fernando et al., 20206)/L) or leukocytosis (>10 × 10(Fernando et al., 20206)/L); and purulent sputum. We also used 6 other definitions estimating the risk of hospital mortality. RESULTS: The frequency of ICU-acquired pneumonia varied by definition: the trial primary outcome VAP (21.6%), Clinical Pulmonary Infection Score (CPIS) (24.9%), American College Chest Physicians (ACCP) (25.0%), International Sepsis Forum (ISF) (24.4%), Reducing Oxidative Stress Study (REDOXS) (17.6%), Centers for Disease Control (CDC) (7.8%), and invasively microbiologically confirmed (1.9%). The trial primary outcome VAP (HR 1.31 [1.08, 1.60]), ISF (HR 1.32 [1.09,1.60]), CPIS (HR 1.30 [1.08,1.58]) and ACCP definitions (HR 1.22 [1.00,1.47]) were associated with hospital mortality. CONCLUSIONS: Rates of ICU-acquired pneumonia vary by definition and are associated with differential increased risk of death.

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.

Prophylactic acid suppressants in patients with primary neurologic injury: A systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Neurocritical care patients are at risk of stress-induced gastrointestinal ulceration. We performed a systematic review and meta-analysis of stress ulcer prophylaxis (SUP) in critically ill adults admitted with a primary neurologic injury. MATERIALS AND METHODS: We included randomized controlled trials (RCTs) comparing SUP with histamine-2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) to placebo/no prophylaxis, as well as to each other. The primary outcome was in-ICU gastrointestinal bleeding (GIB). Predefined secondary outcomes were all-cause 30-day mortality, ICU length of stay (LOS), nosocomial pneumonia, and other complications. RESULTS: We identified 14 relevant trials enrolling 1036 neurocritical care patients; 11 trials enrolling 930 patients were included in the meta-analysis. H2RAs resulted in a lower incidence of GIB as compared to placebo or no prophylaxis (Risk ratio [RR] 0.42, 95% CI 0.30-0.58; p < 0.001); PPIs with a lower risk of GIB compared to placebo/no prophylaxis (RR 0.37, 95% CI 0.23-0.59; p < 0.001). No significant difference was observed in GIB comparing PPIs with H2RAs (RR 0.53, 95% CI 0.26-1.06; p = 0.07; I2 = 0%). CONCLUSIONS: In neurocritical care patients, the overall high or unclear risk of bias of individual trials, the low event rates, and modest sample sizes preclude strong clinical inferences about the utility of SUP.