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.

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.

Association between supportive interventions and healthcare utilization and outcomes in patients on long-term prescribed opioid therapy presenting to acute healthcare settings: a systematic review and meta-analysis.

BACKGROUND: Long-term prescription of opioids by healthcare professionals has been linked to poor individual patient outcomes and high resource utilization. Supportive strategies in this population regarding acute healthcare settings may have substantial impact. METHODS: We performed a systematic review and meta-analysis of primary studies. The studies were included according to the following criteria: 1) age 18 and older; 2) long-term prescribed opioid therapy; 3) acute healthcare setting presentation from a complication of opioid therapy; 4) evaluating a supportive strategy; 5) comparing the effectiveness of different interventions; 6) addressing patient or healthcare related outcomes. We performed a qualitative analysis of supportive strategies identified. We pooled patient and system related outcome data for each supportive strategy. RESULTS: A total of 5664 studies were screened and 19 studies were included. A total of 9 broad categories of supportive strategies were identified. Meta-analysis was performed for the "supports for patients in pain" supportive strategy on two system-related outcomes using a ratio of means. The number of emergency department (ED) visits were significantly reduced for cohort studies (n = 6, 0.36, 95% CI [0.20-0.62], I2 = 87%) and randomized controlled trials (RCTs) (n = 3, 0.71, 95% CI [0.61-0.82], I2 = 0%). The number of opioid prescriptions at ED discharge was significantly reduced for RCTs (n = 3, 0.34, 95% CI [0.14-0.82], I2 = 78%). CONCLUSION: For patients presenting to acute healthcare settings with complications related to long-term opioid therapy, the intervention with the most robust data is "supports for patients in pain".

Frailty and Aging: How the Danish Experience Might Inform Canada.

Scandinavian countries are widely acknowledged as leaders in innovative models of care for their aging populations. To learn what might be potentially applicable to the health system in Canada, the Canadian Frailty Network (CFN) led a contingent of government, administrative, research and patient representatives to Denmark to directly observe Danish approaches for providing healthcare for older adults living with frailty. In this paper and based on what we learned from these observations, we discuss healthcare challenges faced by Canada's aging population for which Danish strategies provide clues as to where and how to improve care and system efficiencies, thereby maximizing the value of Canadian healthcare.

Enabling Healthy Aging to AVOID Frailty in Community Dwelling Older Canadians.

The Canadian population is aging. With aging, biological and social changes occur increasing the risk of developing chronic conditions and functional loss leading to frailty. Older adults living with frailty are more vulnerable to minor stressors, take longer to recover from illness, and have difficulty participating in daily activities. The Canadian Frailty Network's (CFN) mission is to improve the lives of older adults living with frailty. In September 2019, CFN launched the Activity & Exercise, Vaccination, Optimization of medications, Interaction & Socialization, and Diet & Nutrition (AVOID) Frailty public health campaign to promote assessing and reducing risk factors leading to the development of frailty. As part of the campaign, CFN held an Enabling Healthy Aging Symposium with 36 stakeholders from across Canada. Stakeholders identified individual and community-level opportunities and challenges for the enablement of healthy aging and frailty mitigation, as part of a focused consultative process. Stakeholders ranked the three most important challenges and opportunities at the individual and community levels for implementing AVOID Frailty recommendations. Concrete actions, further research areas, policy changes, and existing resources/programs to enhance the AVOID Frailty campaign were identified. The results will help inform future priorities and behaviour change strategies for healthy aging in Canada.

Research interrupted: applying the CONSERVE 2021 Statement to a randomized trial of rehabilitation during critical illness affected by the COVID-19 pandemic.

RATIONALE: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) statement as a framework to report the impact of the pandemic on CYCLE and describe our mitigation approaches. METHODS: On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy) and collect the primary outcome (physical function 3-days post-ICU discharge) and 90-day outcomes. We advised sites to prioritize data for the study's primary outcome. We sought feedback on pandemic barriers related to trial procedures. RESULTS: Our main Methods Centre mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, developing standardized internal tools focused on high-risk points in the protocol for monitoring patient progress, data entry, and validation, and providing guidance to conduct some research activities remotely. For study sites, our strategies included determining how institutional pandemic research policies applied to CYCLE, communicating with the Methods Centre about capacity to continue any part of the research, and developing contingency plans to ensure the protocol was delivered as intended. From 15 active sites (12 Canada, 2 US, 1 Australia), 5 patients were still receiving the study intervention in ICUs, 6 required primary outcomes, and 17 required 90-day assessments. With these mitigation strategies, we attempted 100% of ICU interventions, 83% of primary outcomes, and 100% of 90-day assessments per our protocol. CONCLUSIONS: We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that it also provides a helpful framework for reporting mitigation strategies with the goal of improving research transparency and trial management. TRIAL REGISTRATION: NCT03471247. Registered on March 20, 2018.

Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation.

OBJECTIVE: Procalcitonin may be associated with reduced antibiotic usage compared to usual care. However, individual randomized controlled trials testing this hypothesis were too small to rule out harm, and the full cost-benefit of this strategy has not been evaluated. The purpose of this analysis was to evaluate the effect of a procalcitonin-guided antibiotic strategy on clinical and economic outcomes. INTERVENTIONS: The use of procalcitonin-guided antibiotic therapy. METHODS AND MAIN RESULTS: We searched computerized databases, reference lists of pertinent articles, and personal files. We included randomized controlled trials conducted in the intensive care unit that compared a procalcitonin-guided strategy to usual care and reported on antibiotic utilization and clinically important outcomes. Results were qualitatively and quantitatively summarized. On the basis of no effect in hospital mortality or hospital length of stay, a cost or cost-minimization analysis was conducted using the costs of procalcitonin testing and antibiotic acquisition and administration. Costs were determined from the literature and are reported in 2009 Canadian dollars. Five articles met the inclusion criteria. Procalcitonin-guided strategies were associated with a significant reduction in antibiotic use (weighted mean difference -2.14 days, 95% confidence interval -2.51 to -1.78, p < .00001). No effect was seen of a procalcitonin-guided strategy on hospital mortality (risk ratio 1.06, 95% confidence interval 0.86-1.30, p = .59; risk difference 0.01, 95% confidence interval -0.04 to +0.07, p = .61) and intensive care unit and hospital lengths of stay. The cost model revealed that, for the base case scenario (daily price of procalcitonin Can$49.42, 6 days of procalcitonin measurement, and 2-day difference in antibiotic treatment between procalcitonin-guided therapy and usual care), the point at which the cost of testing equals the cost of antibiotics saved is when daily antibiotics cost Can$148.26 (ranging between Can$59.30 and Can$296.52 on the basis of different assumptions in sensitivity analyses). CONCLUSIONS: Procalcitonin-guided antibiotic therapy is associated with a reduction in antibiotic usage that, under certain assumptions, may reduce overall costs of care. However, the overall estimate cannot rule out a 7% increase in hospital mortality.

Carbapenem Antibiotics for the Empiric Treatment of Nosocomial Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: Previous meta-analyses suggested that treating hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), with empiric carbapenems was associated with lower mortality rates but higher rates of clinical failure for pseudomonal pneumonia. This study was an updated meta-analysis with sensitivity analyses and meta-regression to better understand the impact of carbapenem use in HAP/VAP. RESEARCH QUESTION: What is the efficacy of carbapenems for empiric treatment of nosocomial pneumonia? STUDY DESIGN AND METHODS: Databases were searched for randomized controlled studies evaluating empiric treatment for HAP and/or VAP, and studies were included comparing carbapenem- vs non-carbapenem-containing regimens. The primary outcome was all-cause mortality. Secondary outcomes included subgroup stratification and resistance development. RESULTS: Of 9,140 references, 20 trials enrolling 5,489 patients met inclusion criteria. For mortality, carbapenem use had a risk ratio (RR) of 0.84 (95% CI, 0.74-0.96; P = .01). Stratified according to VAP proportion (< 33%, 33%-66%, and > 66%), RRs were 0.95 (95% CI, 0.77-1.17; P = .66), 0.78 (95% CI, 0.57-1.07; P = .13), and 0.81 (95% CI, 0.65-0.99; P = .04), respectively. Stratified according to severity, only groups with Acute Physiology and Chronic Health Evaluation II scores < 14 and between 14 and 17 showed mortality benefit (RRs of 0.64 [95% CI, 0.45-0.92; P = .01] and 0.77 [95% CI, 0.61-0.97; P = .03]). Meta-regression did not show an association between Pseudomonas prevalence and mortality (P = .44). Carbapenem use showed a trend toward developing resistance (RR, 1.40; 95% CI, 0.95-2.06; P = .09) and a 96% probability of resistance emergence. INTERPRETATION: Carbapenem-based empiric regimens were associated with lower mortality rates compared with non-carbapenems, largely driven by trials of VAP. The mortality effect was not observed in trials with high disease severity and was not associated with Pseudomonas. The mortality difference was observed mainly in studies that used ceftazidime as control. There was a trend toward increasing resistance associated with carbapenems. TRIAL REGISTRY: International Prospective Register of Systematic Reviews; No. CRD42018093602; URL: https://www.crd.york.ac.uk/prospero/.

Prognostic association of frailty with post-arrest outcomes following cardiac arrest: A systematic review and meta-analysis.

OBJECTIVE: To synthesize the current evidence examining the association between frailty and a series of post-arrest outcomes following the provision of cardiopulmonary resuscitation (CPR). DATA SOURCES: We searched MEDLINE, PubMed (exclusive of MEDLINE), EMBASE, CINAHL, and Web of Science from inception to August 2020 for observational studies that examined an association between frailty and post-arrest health outcomes, including in-hospital and post-discharge mortality. We conducted citation tracking for all eligible studies. STUDY SELECTION: Our search yielded 20,480 citations after removing duplicate records. We screened titles, abstracts and full-texts independently and in duplicate. DATA EXTRACTION: The prognosis research strategy group (PROGRESS) and the critical appraisal and data extraction for systematic review of prediction modelling studies (CHARMS) guidelines were followed. Study and outcome-specific risk of bias were assessed using the Quality in Prognosis Studies (QUIPS) instrument. We rated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) recommendations for prognostic factor research. DATA SYNTHESIS: Four studies were included in this review and three were eligible for statistical pooling. Our sample comprised 1,134 persons who experienced in-hospital cardiac arrest (IHCA). The mean age of the sample was 71 years. The study results were pooled according to the specific frailty instrument. Three studies used the Clinical Frailty Scale (CFS) and adjusted age (our minimum confounder); the presence of frailty was associated with an approximate three-fold increase in the odds of dying in-hospital after IHCA (aOR = 2.93; 95% CI = 2.43-3.53, high certainty). Frailty was also associated with decreased incidence of ROSC (return of spontaneous circulation) and discharge home following IHCA. One study with high risk of bias used the Hospital Frailty Risk Score and reported a 43% decrease in the odds of discharge home for patients with frailty following IHCA. CONCLUSION: High certainty evidence was found for an association between frailty and in-hospital mortality following IHCA. Frailty is a robust prognostic factor that contributes valuable information and can inform shared-decision making and policies surrounding advance care directives. Registration: PROSPERO Registration # CRD42020212922.

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol.

INTRODUCTION: Bloodstream infections are a leading cause of mortality and morbidity; the duration of treatment for these infections is understudied. METHODS AND ANALYSIS: We will conduct an international, multicentre randomised clinical trial of shorter (7 days) versus longer (14 days) antibiotic treatment among hospitalised patients with bloodstream infections. The trial will include 3626 patients across 60 hospitals and 6 countries. We will include patients with blood cultures confirming a pathogenic bacterium after hospital admission. Exclusion criteria will include patient factors (severe immunosuppression), infection site factors (endocarditis, osteomyelitis, undrained abscesses, infected prosthetic material) and pathogen factors (Staphylococcus aureus, Staphylococcus lugdunensis, Candida and contaminant organisms). We will leave the selection of specific antibiotics, doses and route of delivery to the discretion of treating physicians; no placebo control will be used given the diversity of pathogens and sources of bacteraemia. The intervention will be assignment of treatment duration to be 7 versus 14 days. We will minimise selection bias via central randomisation with variable block sizes, with concealed allocation until day 7 of adequate antibiotic treatment. The primary outcome is 90-day survival; we will test whether 7 days is non-inferior to 14 days of treatment, with a non-inferiority margin of 4% absolute mortality. Secondary outcomes include hospital and intensive care unit (ICU) mortality, relapse rates of bacteraemia, hospital and ICU length of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile infection, antibiotic allergy and adverse events and colonisation/infection with antibiotic-resistant organisms. ETHICS AND DISSEMINATION: The study has been approved by the ethics review board at each participating site. Sunnybrook Health Sciences Centre is the central ethics committee. We will disseminate study results via the Canadian Critical Care Trials Group and other collaborating networks to set the global paradigm for antibiotic treatment duration for non-staphylococcal Gram-positive, Gram-negative and anaerobic bacteraemia, among patients admitted to hospital. TRIAL REGISTRATION NUMBER: The BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) trial was registered at www.clinicaltrials.gov (registration number: NCT03005145).

Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is an important patient safety issue in critically ill patients. PURPOSE: To develop an evidence-based guideline for the prevention of VAP. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. STUDY SELECTION: The authors systematically searched for relevant randomized, controlled trials and systematic reviews that involved mechanically ventilated adults and were published before 1 April 2003. DATA EXTRACTION: Physical, positional, and pharmacologic interventions that may influence the development of VAP were considered. Independently and in duplicate, the authors scored the validity of trials; the effect size and confidence intervals; the homogeneity of results; and safety, feasibility, and economic issues. DATA SYNTHESIS: Recommended: The orotracheal route of intubation, changes of ventilator circuits only for each new patient and if the circuits are soiled, use of closed endotracheal suction systems that are changed for each new patient and as clinically indicated, heat and moisture exchangers in the absence of contraindications, weekly changes of heat and moisture exchangers, and semi-recumbent positioning in the absence of contraindications. Consider subglottic secretion drainage and kinetic beds. Not recommended: Sucralfate to prevent VAP in patients at high risk for gastrointestinal bleeding and topical antibiotics to prevent VAP. Because of insufficient or conflicting evidence, no recommendations were made about systematically searching for maxillary sinusitis, chest physiotherapy, the timing of tracheostomy, prone positioning, prophylactic intravenous antibiotics, or intravenous plus topical antibiotics. LIMITATIONS: No formal economic analysis was performed, and patient perspectives were not considered. CONCLUSION: If effectively implemented, this guideline may decrease the morbidity, mortality, and costs of VAP in mechanically ventilated patients.

Implementation and Evaluation of a Wiki Involving Multiple Stakeholders Including Patients in the Promotion of Best Practices in Trauma Care: The WikiTrauma Interrupted Time Series Protocol.

BACKGROUND: Trauma is the most common cause of mortality among people between the ages of 1 and 45 years, costing Canadians 19.8 billion dollars a year (2004 data), yet half of all patients with major traumatic injuries do not receive evidence-based care, and significant regional variation in the quality of care across Canada exists. Accordingly, our goal is to lead a research project in which stakeholders themselves will adapt evidence-based trauma care knowledge tools to their own varied institutional contexts and cultures. We will do this by developing and assessing the combined impact of WikiTrauma, a free collaborative database of clinical decision support tools, and Wiki101, a training course teaching participants how to use WikiTrauma. WikiTrauma has the potential to ensure that all stakeholders (eg, patients, clinicians, and decision makers) can all contribute to, and benefit from, evidence-based clinical knowledge about trauma care that is tailored to their own needs and clinical setting. OBJECTIVE: Our main objective will be to study the combined effect of WikiTrauma and Wiki101 on the quality of care in four trauma centers in Quebec. METHODS: First, we will pilot-test the wiki with potential users to create a version ready to test in practice. A rapid, iterative prototyping process with 15 health professionals from nonparticipating centers will allow us to identify and resolve usability issues prior to finalizing the definitive version for the interrupted time series. Second, we will conduct an interrupted time series to measure the impact of our combined intervention on the quality of care in four trauma centers that will be selected-one level I, one level II, and two level III centers. Participants will be health care professionals working in the selected trauma centers. Also, five patient representatives will be recruited to participate in the creation of knowledge tools destined for their use (eg, handouts). All participants will be invited to complete the Wiki101 training and then use, and contribute to, WikiTrauma for 12 months. The primary outcome will be the change over time of a validated, composite, performance indicator score based on 15 process performance indicators found in the Quebec Trauma Registry. RESULTS: This project was funded in November 2014 by the Canadian Medical Protective Association. We expect to start this trial in early 2015 and preliminary results should be available in June 2016. Two trauma centers have already agreed to participate and two more will be recruited in the next months. CONCLUSIONS: We expect that this study will add important and unique evidence about the effectiveness, safety, and cost savings of using collaborative platforms to adapt knowledge implementation tools across jurisdictions.