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.

Follicle-Stimulating Hormone Exacerbates Cardiovascular Disease in the Presence of Low or Castrate Testosterone Levels.

Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHß-/-:low-density lipoprotein receptor (LDLR)-/- mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR-/- mice, but not following FSH delivery. Smaller plaque burden in LDLR-/- mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHß-/-:LDLR-/- mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.

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).

Proton pump inhibitors for gastrointestinal bleeding prophylaxis in critically ill patients: A systematic review protocol.

BACKGROUND: Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for preventing upper gastrointestinal bleeding in critically ill patients. However, concerns have arisen about the possible harms of using PPIs, including potentially increased risk of pneumonia, Clostridioides difficile infection, and more seriously, an increased risk of death in the most severely ill patients. Triggered by the REVISE trial, which is a forthcoming large randomized trial comparing pantoprazole to placebo in invasively mechanically ventilated patients, we will conduct this systematic review to evaluate the efficacy and safety of PPIs versus no prophylaxis for critically ill patients. METHODS: We will systematically search randomized trials that compared gastrointestinal bleeding prophylaxis with PPIs versus placebo or no prophylaxis in adults in the intensive care unit (ICU). Pairs of reviewers will independently screen the literature, and for those eligible trials, extract data and assess risk of bias. We will perform meta-analyses using a random-effects model, and calculate relative risks for dichotomous outcomes and mean differences for continuous outcomes, and the associated 95% confidence intervals. We will conduct subgroup analysis to explore whether the impact of PPIs on mortality differs in more and less severely ill patients. We will assess certainty of evidence using the GRADE approach. DISCUSSION: This systematic review will provide the most up-to-date evidence regarding the merits and limitations of stress ulcer prophylaxis with PPIs in critically ill patients in contemporary practice.

One-year Outcomes after Discharge from Noncardiac Surgery and Association between Predischarge Complications and Death after Discharge: Analysis of the VISION Prospective Cohort Study.

BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.

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.

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].

Reamed compared with unreamed nailing of tibial shaft fractures: Does the initial method of nail insertion influence outcome in patients requiring reoperations?

BACKGROUND: Patients with a tibial shaft fracture experiencing their first postoperative complication following treatment with intramedullary nails may be at greater risk of subsequent complications than the whole population. We aimed to determine whether the initial method of nail insertion influences outcome in patients with a tibial shaft fracture requiring multiple reoperations. METHODS: Using the Study to Prospectively Evaluate Reamed Intramedullary Nails in Tibial Shaft Fractures trial data, we categorized patients as those not requiring reoperation, those requiring a single reoperation and those requiring multiple reoperations, and we compared them by nail insertion technique (reamed v. unreamed) and fracture type (open v. closed). We then determined the number of patients whose first reoperation was in response to infection, and we compared other clinical outcomes between the reamed and unreamed groups. RESULTS: Among 1226 patients included in this analysis, 175 (14.27%) experienced a single reoperation and 44 patients (3.59%) underwent multiple reoperations. Nail insertion techniques (reamed v. unreamed) did not play a role in the need to perform multiple reoperations. Seventy-five percent of patients requiring multiple reoperations had open tibial shaft fractures. An equal number of these were reamed and unreamed insertions. The majority of patients had their course complicated by infection and almost 50% of patients whose first reoperation was for infection required more than 2 reoperations for management. The rest required multiple procedures for nonunion or bone loss. CONCLUSION: Our findings corroborate those of other studies, in which open fracture type rather than nail insertion technique was found to be the cause of morbidity following intramedullary nailing of tibial fractures. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov, no. NCT00038129.

Myocardial Injury After Noncardiac Surgery in Major General Surgical Patients a Prospective Observational Cohort Study.

OBJECTIVE: The objective of this study was to determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in major general surgery patients. BACKGROUND: MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in major general surgical patients have not been described. METHODS: This was an international prospective cohort study of a representative sample of 22,552 noncardiac surgery patients 45 years or older, of whom 4490 underwent major general surgery in 24 centers in 13 countries. All patients had fifth-generation plasma high-sensitivity troponin T (hsTnT) concentrations measured during the first 3 postoperative days. MINS was defined as a hsTnT of 20-65 ng/L and absolute change >5 ng/L or hsTnT ≥65 ng/L secondary to ischemia. The objectives of the present study were to determine (1) whether MINS is prognostically important in major general surgical patients, (2) the clinical characteristics of major general surgical patients with and without MINS, (3) the 30-day outcomes for major general surgical patients with and without MINS, and (4) the proportion of MINS that would have gone undetected without routine postoperative monitoring. RESULTS: The incidence of MINS in the major general surgical patients was 16.3% (95% CI, 15.3-17.4%). Thirty-day all-cause mortality in the major general surgical cohort was 6.8% (95% CI, 5.1%-8.9%) in patients with MINS compared with 1.2% (95% CI, 0.9%-1.6%) in patients without MINS ( P <0.01). MINS was independently associated with 30-day mortality in major general surgical patients (adjusted odds ratio 4.7, 95% CI, 3.0-7.4). The 30-day mortality was higher both among MINS patients with no ischemic features (ie, no ischemic symptoms or electrocardiogram findings) (5.4%, 95% CI, 3.7%-7.7%) and among patients with 1 or more clinical ischemic features (10.6%, 95% CI, 6.7%-15.8%). The proportion of major general surgical patients who had MINS without ischemic symptoms was 89.9% (95% CI, 87.5-92.0). CONCLUSIONS: Approximately 1 in 6 patients experienced MINS after major general surgery. MINS was independently associated with a nearly 5-fold increase in 30-day mortality. The vast majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.

Sex differences in thromboprophylaxis of the critically ill: a secondary analysis of a randomized trial.

PURPOSE: Venous thromboembolism (VTE) is a common complication of critical illness. Sex- or gender-based analyses are rarely conducted and their effect on outcomes is unknown. We assessed for an effect modification of thromboprophylaxis (dalteparin or unfractionated heparin [UFH]) by sex on thrombotic (deep venous thrombosis [DVT], pulmonary embolism [PE], VTE) and mortality outcomes in a secondary analysis of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT). METHODS: We conducted unadjusted analyses using Cox proportional hazards analysis, stratified by centre and admission diagnostic category, including sex, treatment, and an interaction term. Additionally, we performed adjusted analyses and assessed the credibility of our findings. RESULTS: Critically ill female (n = 1,614) and male (n = 2,113) participants experienced similar rates of DVT, proximal DVT, PE, any VTE, ICU death, and hospital death. In unadjusted analyses, we did not find significant differences in treatment effect favouring males (vs females) treated with dalteparin (vs UFH) for proximal leg DVT, any DVT, or any PE, but found a statistically significant effect (moderate certainty) favouring dalteparin in males for any VTE (males: hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96 vs females: HR, 1.16; 95% CI, 0.81 to 1.68; P = 0.04). This effect remained after adjustment for baseline characteristics (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.17; 95% CI, 0.81 to 1.68; P = 0.04) and weight (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.20; 95% CI, 0.83 to 1.73; P = 0.03). We did not identify a significant effect modification by sex on mortality. CONCLUSIONS: We found an effect modification by sex of thromboprophylaxis on VTE in critically ill patients that requires confirmation. Our findings highlight the need for sex- and gender-based analyses in acute care research.

RéSUMé: OBJECTIF: La maladie thromboembolique veineuse (MTEV) est une complication fréquente au cours des maladies critiques. Des analyses basées sur le sexe ou le genre sont rarement effectuées et leur effet sur les critères d'évaluation est inconnu. Nous avons évalué une modification de l'effet de la thromboprophylaxie (daltéparine ou héparine non fractionnée [HNF]) selon le sexe sur la maladie thrombotique (thrombose veineuse profonde [TVP], embolie pulmonaire [EP], MTEV) et sur les critères de mortalité au cours d'une analyse secondaire de l'étude PROTECT (essai de prophylaxie de la thromboembolie en soins critiques). MéTHODE: Nous avons réalisé des analyses non ajustées au moyen d'une analyse des risques proportionnels de Cox, stratifiées par site et catégorie diagnostique à l'admission, incluant le sexe, le traitement et un terme d'interaction. Nous avons aussi réalisé des analyses ajustées et avons évalué la crédibilité de nos constatations. RéSULTATS: Les participant·es dans un état critique de sexe féminin (n = 1 614) et masculin (n = 2 113) ont présenté des taux semblables de TVP, EP, et MTEV de tout type, de décès en soins intensifs et de décès en milieu hospitalier. Nous n'avons pas trouvé de différences significatives dans les analyses non ajustées en faveur des hommes (par rapport aux femmes) traités par la daltéparine (par rapport à l'HNF) pour la TVP de la cuisse, la TVP de tout type, ou tout type d'EP; en revanche, nous avons trouvé un effet statistiquement significatif (certitude modérée) en faveur de la daltéparine pour la MTEV de tout type (hommes : rapport de risque [RR], 0,71; intervalle de confiance [IC] à 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,16; IC 95 %, 0,81 à 1,68; P = 0,04). Cet effet a persisté après ajustement pour les caractéristiques à l'inclusion (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,17; IC 95 %, 0,81 à 1,68; P = 0,04) et le poids (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,20; IC 95 %, 0,83 à 1,73; P = 0,03). Nous n'avons pas identifié de modification significative de l'effet en fonction du sexe sur la mortalité. CONCLUSION: Nous avons trouvé une modification de l'effet en fonction du sexe sur la thromboprophylaxie sur la MTEV chez les patient·es en état critique; cette constatation nécessite une confirmation. Nos constatations soulignent le besoin d'analyses en fonction du sexe et du genre dans la recherche sur les soins aigus.

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).

Association of Preoperative Growth Differentiation Factor-15 Concentrations and Postoperative Cardiovascular Events after Major Noncardiac Surgery.

BACKGROUND: The association between growth differentiation factor-15 concentrations and cardiovascular disease has been well described. The study hypothesis was that growth differentiation factor-15 may help cardiac risk stratification in noncardiac surgical patients, in addition to clinical evaluation. METHODS: The objective of the study was to determine whether preoperative serum growth differentiation factor-15 is associated with the composite primary outcome of myocardial injury after noncardiac surgery and vascular death at 30 days and can improve cardiac risk prediction in noncardiac surgery. This is a prospective cohort study of patients 45 yr or older having major noncardiac surgery. The association between preoperative growth differentiation factor-15 and the primary outcome was determined after adjusting for the Revised Cardiac Risk Index. Preoperative N-terminal-pro hormone brain natriuretic peptide was also added to compare predictive performance with growth differentiation factor-15. RESULTS: Between October 27, 2008, and October 30, 2013, a total of 5,238 patients were included who had preoperative growth differentiation factor-15 measured (median, 1,325; interquartile range, 880 to 2,132 pg/ml). The risk of myocardial injury after noncardiac surgery and vascular death was 99 of 1,705 (5.8%) for growth differentiation factor-15 less than 1,000 pg/ml, 161 of 1,332 (12.1%) for growth differentiation factor-15 1,000 to less than 1,500 pg/ml, 302 of 1476 (20.5%) for growth differentiation factor-15 1,500 to less than 3,000 pg/ml, and 247 of 725 (34.1%) for growth differentiation factor-15 concentrations 3,000 pg/ml or greater. Compared to patients who had growth differentiation factor-15 concentrations less than 1,000 pg/ml, the corresponding adjusted hazard ratio for each growth differentiation factor-15 category was 1.93 (95% CI, 1.50 to 2.48), 3.04 (95% CI, 2.41 to 3.84), and 4.8 (95% CI, 3.76 to 6.14), respectively. The addition of growth differentiation factor-15 improved cardiac risk classification by 30.1% (301 per 1,000 patients) compared to Revised Cardiac Risk Index alone. It also provided additional risk classification beyond the combination of preoperative N-terminal-pro hormone brain natriuretic peptide and Revised Cardiac Risk Index (16.1%; 161 per 1,000 patients). CONCLUSIONS: Growth differentiation factor-15 is strongly associated with 30-day risk of major cardiovascular events and significantly improved cardiac risk prediction in patients undergoing noncardiac surgery.

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.

High-sensitivity Troponin I Predicts Major Cardiovascular Events after Non-Cardiac Surgery: A Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Substudy.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS), based on measurement of troponin T, is associated with perioperative major adverse cardiovascular events (MACE). We therefore determined the high-sensitivity troponin I (hsTnI) thresholds associated with 30 day MACE after non-cardiac surgery. METHODS: We performed a nested biobank cohort study of 4553 patients from the Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Study. We measured hsTnI (ADVIA Centaur® hsTnI assay) on postoperative days 1 to 3 in patients ≥45 years undergoing non-cardiac surgery. An iterative Cox proportional hazard model determined peak postoperative hsTnI thresholds independently associated with MACE (i.e., death, myocardial infarction occurring on postoperative day 4 or after, non-fatal cardiac arrest, or congestive heart failure) within 30 days after surgery. RESULTS: MACE occurred in 89/4545 (2.0%) patients. Peak hsTnI values of <75 ng/L, 75 ng/L to <1000 ng/L, and ≥1000 ng/L were associated with 1.2% (95% CI, 0.9-1.6), 7.1% (95% CI, 4.8-10.5), and 25.9% (95% CI, 16.3-38.4) MACE, respectively. Compared to peak hsTnI <75 ng/L, values 75 ng/L to <1000 ng/L and ≥1000 ng/L were associated with adjusted hazard ratios (aHR) of 4.53 (95% CI, 2.75-7.48) and 16.17 (95% CI, 8.70-30.07), respectively. MACE was observed in 9% of patients with peak hsTnI ≥75 ng/L vs 1% in patients with peak hsTnI <75 ng/L (aHR 5.76; 95% CI, 3.64-9.11). A peak hsTnI ≥75 ng/L was associated with MACE in the presence (aHR 9.35; 95% CI, 5.28-16.55) or absence (aHR 3.99; 95% CI, 2.19-7.25) of ischemic features of myocardial injury. CONCLUSION: A peak postoperative hsTnI ≥75 ng/L was associated with >5-fold increase in the risk of 30 days MACE compared to levels <75 ng/L. This threshold could be used for MINS diagnosis when the ADVIA Centaur hsTnI assay is used.Clinicaltrials.gov Registration Number: NCT00512109.

Change in Gustilo-Anderson classification at time of surgery does not increase risk for surgical site infection in patients with open fractures: A secondary analysis of a multicenter, prospective randomized controlled trial.

Introduction: Open fractures represent a major source of morbidity. Surgical site infections (SSIs) after open fractures are associated with a high rate of reoperations and hospitalizations, which are associated with a lower health-related quality of life. Early antibiotic delivery, typically chosen through an assessment of the size and contamination of the wound, has been shown to be an effective technique to reduce the risk of SSI in open fractures. The Gustilo-Anderson classification (GAC) was devised as a grading system of open fractures after a complete operative debridement of the wound had been undertaken but is commonly used preoperatively to help with the choice of initial antibiotics. Incorrect preoperative GAC, leading to less aggressive initial management, may influence the risk of SSI after open fracture. The objectives of this study were to determine (1) how often the GAC changed from the initial to definitive grading, (2) the injury and patient characteristics associated with increases and decreases of the GAC, and (3) whether a change in GAC was associated with an increased risk of SSI. Methods: Using data from the FLOW trial, a large multicenter randomized study, we used descriptive statistics to quantify how frequently the GAC changed from the initial to definitive grading. We used regression models to determine which injury and patient characteristics were associated with increases and decreases in GAC and whether a change in GAC was associated with SSI. Results: Of the 2420 participants included, 305 participants had their preoperative GAC change (12.6%). The factors associated with upgrading the GAC (from preoperative score to the definitive assessment) included fracture sites other than the tibia, bone loss at presentation, width of wound, length of wound, and skin loss at presentation. However, initial misclassification of type III fractures as type II fractures was not associated with an increased risk of SSI (P = 0.14). Conclusions: When treating patients with open fracture wounds, surgeons should consider that 12% of all injuries may initially be misclassified when using the GAC, particularly fractures that have bone loss at presentation or those located in sites different than the tibia. However, even in misclassified fractures, it did not seem to increase the risk of SSI.

Enhancing end of life care on general internal medical wards: the 3 Wishes Project.

BACKGROUND: Initially developed in the intensive care unit (ICU) at St. Joseph's Healthcare Hamilton (SJHH) the 3 Wishes Project (3WP) provides personalized, compassionate care to dying patients and their families. The objective of this study was to develop and evaluate 3WP expansion strategies for patients cared for on General Internal Medicine (GIM) wards in our hospital. METHODS: From January 2020-November 2021, we developed a phased, multicomponent approach for program expansion. We enrolled patients on the GIM wards who had a high probability of dying in hospital, then elicited, implemented, and documented wishes for them or their families. Data were analyzed descriptively. RESULTS: From March 2020 to November 2020, we implemented staff education and engagement activities, created an Expansion Coordinator position, held strategic consultations, and offered enabling resources. From March 2020 to November 2021, we enrolled 62 patients and elicited 281 wishes (median [1st, 3rd quartiles] 4 [4, 5] wishes/patient). The most common wish categories were personalizing the environment (67 wishes, 24%), rituals and spiritual support (42 wishes, 15%), and facilitating connections (39 wishes, 14%). The median [1st, 3rd] cost/patient was $0 [0, $10.00] (range $0 to $86); 91% of wishes incurred no cost to the program. CONCLUSIONS: The formal expansion of the 3WP on GIM wards has been successful despite COVID-19 pandemic disruptions. While there is still work ahead, these data suggest that implementing the 3WP on the GIM wards is feasible and affordable. Increased engagement of the clinical team during the pandemic suggests that it is positively received.

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.

High-Sensitivity Cardiac Troponin I Thresholds to Identify Myocardial Injury After Noncardiac Surgery: A Cohort Study.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is common and associated with short- and long-term major cardiovascular events. Diagnostic criteria for MINS using Abbott high-sensitivity cardiac troponin I (hs-cTnI) are unknown. METHODS: We performed a prospective cohort study of adults who had in-patient noncardiac surgery and measured hs-cTnI (Abbott Laboratories) on postoperative serum samples collected up to postoperative day 3. The objective was to determine prognostically important hs-cTnI thresholds associated with major cardiac events and death at 30 days after noncardiac surgery. Using Cox proportional iterative analyses, we determined peak postoperative hs-cTnI thresholds associated with the occurrence of the 30-day composite of major cardiac events (ie, nonfatal myocardial infarction after 3 postoperative days, cardiac arrest, and congestive heart failure) and death. RESULTS: Of 3953 included patients, 66 (1.7%) experienced the primary outcome at 30 days. Peak hs-cTnI values and associated incidence of major cardiac events and death were as follows: < 60 ng/L: 1.0% (95% CI 0.7-1.3); 60 to < 700 ng/L: 8.6% (5.6-13.0); and ≥ 700 ng/L: 27.3% (16.4-41.9). Compared with peak hs-cTnI < 60 ng/L, adjusted hazard ratios were 7.54 (95% CI% 4.27-13.32) for hs-cTnI values of 60 to < 700 ng/L and 26.87 (13.27-54.41) for values ≥ 700 ng/L. CONCLUSIONS: Hs-cTnI elevation within the first 3 days after noncardiac surgery independently predicts major cardiac events and death at 30 days. A postoperative hs-cTnI ≥ 60 ng/L was associated with a > 7-fold increase in the risk of subsequent major cardiac events and mortality at 30 days.

Academic and Community ICUs Participating in a Critical Care Randomized Trial: A Comparison of Patient Characteristics and Trial Metrics.

Clinical research in Canada is conducted primarily in "academic" hospitals, whereas most clinical care is provided in "community" hospitals. The objective of this nested observational study was to compare patient characteristics, outcomes, process-of-care variables, and trial metrics for patients enrolled in a large randomized controlled trial who were admitted to academic and community hospitals in Canada. DESIGN: We conducted a preplanned observational study nested within the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT, a randomized controlled trial comparing probiotics to placebo in mechanically ventilated patients) Research Program. SETTING: ICUs. PATIENTS: Mechanically ventilated patients. MEASUREMENTS: We compared patient characteristics, interventions, outcomes, and trial metrics between patients enrolled in PROSPECT from academic and community hospitals. MAIN RESULTS: Participating centers included 34 (82.9%) academic and seven (17.1%) community hospitals, which enrolled 2,203 (86.2%) and 352 (13.8%) patients, respectively. Compared with academic hospitals, patients enrolled in community hospitals were older (mean [sd] 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), had longer ICU stays (median [interquartile range {IQR}], 13 d [8-23 d] vs 11 d [7-8 d]; p = 0.012) and higher mortality (percentage, [95% CI] in the ICU, 30.4% [25.8-35.4%]vs 20.5% [18.9-11.3%]; p = 0.002) and hospital (40.6% [35.6-45.8%] vs 26.1% [24.3-27.9%]; p < 0.001). Trial metrics, including informed consent rate (85.9% vs 76.3%; p = 0.149), mean (sd) monthly enrolment rate (2.1 [1.4] vs 1.1 [0.7]; p = 0.119), and protocol adherence (90.6% vs 91.6%; p = 0.207), were similar between community and academic ICUs. CONCLUSIONS: Community hospitals can conduct high-quality research, with similar trial metrics to academic hospitals. Patient characteristics differed between community and academic hospitals, highlighting the need for broader engagement of community hospitals in clinical research to ensure generalizability of study results.