Exploring the impact of a clinical extern program on readiness to practice.

The COVID-19 pandemic created an increased demand for healthcare professionals across all healthcare sectors globally. Attrition, retirement, delayed graduations, and sick leaves resulted in an inadequate supply of knowledgeable, skilled, and experienced nurses to care for hospitalized patients and help address hospital capacity pressures. In response to this health human resource crisis in Canada, the Ontario Ministry of Health offered hospitals funding to support the employment of Clinical Externs (CEs), that is, students in nursing, respiratory therapy, physiotherapy, occupational therapy medicine, and paramedicine, hired to work as unregulated staff, alongside an inter-professional team. This mixed-methods study evaluated the CE program that was implemented in one large academic hospital. The primary aim was to identify the outcomes of the clinical extern program from the perspectives of CEs, CE coordinators, and clinical leaders. Findings indicate the clinical extern program reinforces student confidence and supports their transition to formal nursing and respiratory therapy roles.

Impact of sample processing delays on plasma markers of inflammation, chemotaxis, cell death, and blood coagulation.

BACKGROUND: Biosampling studies in critically ill patients traditionally involve bedside collection of samples followed by local processing (ie. centrifugation, aliquotting, and freezing) and storage. However, community hospitals, which care for the majority of Canadian patients, often lack the infrastructure for local processing and storage of specimens. A potential solution is a "simplified" biosampling protocol whereby blood samples are collected at the bedside and then shipped to a central site for processing and storage. One potential limitation of this approach is that delayed processing may alter sample characteristics. OBJECTIVE: To determine whether delays in blood sample processing affect the stability of cytokines (IL-6, TNF, IL-10, IFN-γ), chemokines (IL-8, IP-10, MCP-1, MCP-4, MIP-1α, MIP-1ß), cell-free DNA (cfDNA) (released by dying cells), and blood clotting potential in human blood samples. METHODS: Venous blood was collected into EDTA and citrate sample tubes and stored at room temperature (RT) or 4°C for progressive intervals up to 72 hours, prior to processing. Plasma cytokines and chemokines were quantified using single or multiplex immunoassays. cfDNA was measured using Picogreen DNA Quantification. Blood clotting potential was measured using a thrombin generation assay. RESULTS: Blood samples were collected from 9 intensive care unit (ICU) patients and 7 healthy volunteers. Admission diagnoses for the ICU patients included sepsis, trauma, ruptured abdominal aortic aneurysm, intracranial hemorrhage, gastrointestinal bleed, and hyperkalemia. After pre-processing delays of up to 72 hours at RT or 4°C, no significant changes were observed in plasma cytokines, chemokines, cfDNA, or thrombin formation. CONCLUSIONS: Delayed sample processing for up to 72 hours at either RT or 4°C did not significantly affect cytokines, chemokines, cfDNA, or blood clotting potential in plasma samples from healthy volunteers and ICU patients. A "simplified" biosampling protocol is a feasible solution for conducting biosampling research at hospitals without local processing capacity.

Early In-Bed Cycle Ergometry With Critically Ill, Mechanically Ventilated Patients: Statistical Analysis Plan for CYCLE (Critical Care Cycling to Improve Lower Extremity Strength), an International, Multicenter, Randomized Clinical Trial.

BACKGROUND: Survivors of critical illness are at risk of developing physical dysfunction following intensive care unit (ICU) discharge. ICU-based rehabilitation interventions, such as early in-bed cycle ergometry, may improve patients' short-term physical function. OBJECTIVE: Before unblinding and trial database lock, we describe a prespecified statistical analysis plan (SAP) for the CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) randomized controlled trial (RCT). METHODS: CYCLE is a 360-patient, international, multicenter, open-label, parallel-group RCT (1:1 ratio) with blinded primary outcome assessment at 3 days post-ICU discharge. The principal investigator and statisticians of CYCLE prepared this SAP with approval from the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes (including adverse events) and describes the planned primary, secondary, and subgroup analyses. The primary outcome of the CYCLE trial is the Physical Function Intensive Care Unit Test-scored (PFIT-s) at 3 days post-ICU discharge. The PFIT-s is a reliable and valid performance-based measure. We plan to use a frequentist statistical framework for all analyses. We will conduct a linear regression to evaluate the primary outcome, incorporating randomization as an independent variable and adjusting for age (≥65 years versus <65 years) and center. The regression results will be reported as mean differences in PFIT-s scores with corresponding 95% CIs and P values. We consider a 1-point difference in PFIT-s score to be clinically important. Additionally, we plan to conduct 3 subgroup analyses: age (≥65 years versus <65 years), frailty (Baseline Clinical Frailty Scale ≥5 versus <5), and sex (male versus female). RESULTS: CYCLE was funded in 2017, and enrollment was completed in May 2023. Data analyses are complete, and the first results were submitted for publication in 2024. CONCLUSIONS: We developed and present an SAP for the CYCLE RCT and will adhere to it for all analyses. This study will add to the growing body of evidence evaluating the efficacy and safety of ICU-based rehabilitation interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03471247; https://clinicaltrials.gov/ct2/show/NCT03471247 and NCT02377830; https://clinicaltrials.gov/ct2/show/NCT02377830. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/54451.

Characterizing usual-care physical rehabilitation in Canadian intensive care unit patients: a secondary analysis of the Canadian multicentre Critical Care Cycling to Improve Lower Extremity Strength pilot randomized controlled trial.

PURPOSE: Physical rehabilitation (PR) in the intensive care unit (ICU) may improve outcomes for survivors but clinical trial results have been discordant. We hypothesized that discordant results may reflect treatment heterogeneity received by "usual care" comparator groups in PR studies. Usual-care PR is typically underspecified, which is a barrier to comparing results across treatment studies. The primary objective of the present study was to describe the usual-care PR received by critically ill patients enrolled in the Canadian multicentre Critical Care Cycling to Improve Lower Extremity Strength (CYCLE) pilot randomized controlled trial (RCT) of PR. Other objectives were to help contextualize current research and provide data for international comparison. METHODS: In this secondary analysis of the CYCLE pilot RCT, patients were randomized to in-bed cycling and usual-care PR or usual-care PR alone. Physiotherapists documented usual-care PR including therapy received, type of activity, duration, adverse events and consequences, reasons for no PR, and concurrent relevant medical interventions. We characterized usual care using descriptive statistics at the cohort and patient levels. RESULTS: Across seven Canadian centres, 30 patients were randomized to usual-care PR. The median [interquartile range (IQR)] ICU stay was 10 [9-24] days and patients received PR on a median [IQR] of 5 [3-9] days for 23 [17-30] min per day. Eighteen patients (60%) stood, marched, or walked during usual care. Transient adverse events occurred in three patients on 1.5% (3/198) of days and none prompted session termination. CONCLUSIONS: In the usual-care arm of the CYCLE pilot RCT, PR was delivered on half of ICU days and over half of patients stood, marched, or walked. Adverse events during usual-care PR were uncommon. STUDY REGISTRATION: ClinicalTrials.gov ( NCT02377830 ); first posted 4 March 2015.

RéSUMé: OBJECTIF: La réadaptation physique (RP) à l'unité de soins intensifs (USI) pourrait améliorer les devenirs pour les personnes survivantes, mais les résultats des études cliniques sont contradictoires. Nous avons émis l'hypothèse que les résultats contradictoires pourraient refléter l'hétérogénéité des traitements reçus par les groupes de comparaison de « soins standards ¼ dans les études sur la RP. La RP habituelle est généralement sous-spécifiée, ce qui constitue un obstacle à la comparaison des résultats entre les études de traitement. L'objectif principal de la présente étude était de décrire les RP habituelles reçues par les patient·es gravement malades inscrit·es dans l'étude randomisée contrôlée (ERC) multicentrique canadienne pilote sur les RP intitulée CYCLE (Critical Care Cycling to Improve Lower Extremity Strength, soit Cyclisme en soins intensifs pour améliorer la force des membres inférieurs). D'autres objectifs étaient d'aider à contextualiser les recherches actuelles et de fournir des données pour une comparaison internationale. MéTHODE: Dans cette analyse secondaire de l'ERC pilote CYCLE, les patient·es ont été randomisé·es à faire du vélo au lit et de la RP habituelle ou seulement de la RP habituelle. Les physiothérapeutes ont documenté la RP habituelle, y compris la thérapie reçue, le type d'activité, la durée, les événements indésirables et les conséquences, les raisons de l'absence de RP et les interventions médicales pertinentes concomitantes. Nous avons caractérisé les soins standards à l'aide de statistiques descriptives au niveau de la cohorte et de la personne traitée. RéSULTATS: Dans sept centres canadiens, 30 patient·es ont été randomisé·es pour recevoir la RP habituelle. La durée de séjour médiane [écart interquartile (ÉIQ)] aux soins intensifs était de 10 [9-24] jours et les patient·es ont reçu de la RP sur une durée médiane [ÉIQ] de 5 [3-9] jours pendant 23 [17-30] minutes par jour. Dix-huit patient·es (60 %) se sont tenu·es debout, ont marché de façon stationnaire ou ont marché pendant les soins standards. Des effets indésirables transitoires sont survenus chez trois patient·es pendant 1,5 % (3/198) des jours et aucun n'a entraîné l'interruption de la séance. CONCLUSION: Dans le volet soins habituels de l'ERC pilote CYCLE, la réadaptation physique a été dispensée pendant la moitié des jours de soins intensifs et plus de la moitié des patient·es se sont tenu·es debout, ont marché de façon stationnaire ou ont marché. Les événements indésirables lors de la RP habituelle étaient rares. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT02377830 ); première mise en ligne le 4 mars 2015.

Social determinants of health and sepsis: a case-control study.

PURPOSE: We aimed to identify whether social determinants of health (SDoH) are associated with the development of sepsis and assess the differences between individuals living within systematically disadvantaged neighbourhoods compared with those living outside these neighbourhoods. METHODS: We conducted a single-centre case-control study including 300 randomly selected adult patients (100 patients with sepsis and 200 patients without sepsis) admitted to the emergency department of a large academic tertiary care hospital in Hamilton, ON, Canada. We collected data on demographics and a limited set of SDoH variables, including neighbourhood household income, smoking history, social support, and history of alcohol disorder. We analyzed study data using multivariate logistic regression models. RESULTS: The study included 100 patients with sepsis with a median [interquartile range (IQR)] age of 75 [58-84] yr and 200 patients without sepsis with a median [IQR] age of 72 [60-83] yr. Factors significantly associated with sepsis included arrival by ambulance, absence of a family physician, higher Hamilton Early Warning Score, and a recorded history of dyslipidemia. Important SDoH variables, such as individual or household income and race, were not available in the medical chart. In patients with SDoH available in their medical records, no SDoH was significantly associated with sepsis. Nevertheless, compared with their proportion of the Hamilton population, the rate of sepsis cases and sepsis deaths was approximately two times higher among patients living in systematically disadvantaged neighbourhoods. CONCLUSIONS: This study revealed the lack of available SDoH data in electronic health records. Despite no association between the SDoH variables available and sepsis, we found a higher rate of sepsis cases and sepsis deaths among individuals living in systematically disadvantaged neighbourhoods. Including SDoH in electronic health records is crucial to study their effect on the risk of sepsis and to provide equitable care.

RéSUMé: OBJECTIF: Nous avons cherché à déterminer si les déterminants sociaux de la santé (DSS) étaient associés à l'apparition de sepsis et à évaluer les différences entre les personnes vivant dans des quartiers systématiquement défavorisés et celles vivant à l'extérieur de ces quartiers. MéTHODE: Nous avons mené une étude cas témoins monocentrique portant sur 300 patient·es adultes sélectionné·es au hasard (100 personnes atteintes de sepsis et 200 témoins sans sepsis) admis·es au service des urgences d'un grand hôpital universitaire de soins tertiaires à Hamilton, ON, Canada. Nous avons recueilli des données démographiques et un ensemble limité de variables de DSS, y compris le revenu des ménages du quartier, les antécédents de tabagisme, le soutien social et les antécédents de troubles liés à l'alcool. Nous avons analysé les données de l'étude à l'aide de modèles de régression logistique multivariés. RéSULTATS: L'étude a inclus 100 patient·es atteint·es de sepsis avec un âge médian [écart interquartile (ÉIQ)] de 75 [58-84] ans et 200 patient·es sans sepsis avec un âge médian [ÉIQ] de 72 [60-83] ans. Les facteurs significativement associés au sepsis comprenaient l'arrivée en ambulance, l'absence de médecin de famille, un score Hamilton Early Warning Score plus élevé et des antécédents enregistrés de dyslipidémie. D'importantes variables de DSS, telles que le revenu individuel et du ménage et la race, n'étaient pas disponibles dans le dossier médical. Chez les personnes dont les DSS étaient disponibles dans leur dossier médical, aucun DSS n'était significativement associé au sepsis. Néanmoins, comparativement à leur proportion dans la population de Hamilton, le taux de cas de sepsis et de décès dus au sepsis était environ deux fois plus élevé chez les personnes vivant dans des quartiers systématiquement défavorisés. CONCLUSION: Cette étude a révélé le manque de données disponibles sur les DSS dans les dossiers de santé électroniques. Bien qu'il n'y ait pas d'association entre les variables disponibles et le sepsis, nous avons constaté un taux plus élevé de cas de sepsis et de décès dus à la septicémie chez les personnes vivant dans des quartiers systématiquement défavorisés. L'inclusion des DSS dans les dossiers de santé électroniques est cruciale pour étudier leur effet sur le risque de sepsis et pour dispenser des soins équitables.

Statistical analysis plan for the SQUEEZE trial: A trial to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy vs. usual care (SQUEEZE).

Background: The SQUEEZE trial is a multicentred randomized controlled trial which seeks to determine the optimal approach to fluid resuscitation in paediatric septic shock. SQUEEZE also includes a nested translational study, SQUEEZE-D, investigating the value of plasma cell-free DNA for prediction of clinical outcomes. Objective: To present a pre-specified statistical analysis plan (SAP) for the SQUEEZE trial prior to finalizing the trial data set and prior to commencing data analysis. Design: SQUEEZE is a pragmatic, two-arm, open-label, prospective multicentre randomized controlled trial. Setting: Canadian paediatric tertiary care centres. Participants: Paediatric patients with suspected sepsis and persistent signs of shock in need of ongoing resuscitation. Sample size target: 400 participants. Interventions: The trial is designed to compare a fluid-sparing resuscitation strategy to usual care. Main outcome measures: The primary outcome for the SQUEEZE trial is the time to shock reversal (in hours). The primary outcome analysis will assess the difference in time to shock reversal between the intervention and control groups, reported as point estimate with 95% confidence intervals. The statistical test for the primary analysis will be a two-sided t-test. Secondary outcome measures include clinical outcomes and adverse events including measures of organ dysfunction and mortality outcomes. Results: The SAP presented here is reflective of and where necessary clarifies in detail the analysis plan as presented in the trial protocol. The SAP includes a mock CONSORT diagram, figures and tables. Data collection methods are summarized, primary and secondary outcomes are defined, and outcome analyses are described. Conclusions: We have developed a statistical analysis plan for the SQUEEZE Trial for transparency and to align with best practices. Analysis of SQUEEZE Trial data will adhere to the SAP to reduce the risk of bias. Registration: ClinicalTrials.gov identifiers: Definitive trial NCT03080038; Registered Feb 28, 2017. Pilot Trial NCT01973907; Registered Oct 27, 2013.

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

BACKGROUND: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. METHODS: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. RESULTS: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. INTERPRETATION: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock. DATA SOURCES: We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024. STUDY SELECTION: We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration. DATA EXTRACTION: Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. DATA SYNTHESIS: We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47-0.94], low certainty) and hospital length of stay (mean difference [MD] -2.1 d [95% CI, -1.4 to -2.8], low certainty). MB may also reduce duration of vasopressors (MD -31.1 hr [95% CI, -16.5 to -45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1-14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, -0.2% to 2.0%], very low certainty). We did not find any differences in adverse events. CONCLUSIONS: Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed. REGISTRATION: Center for Open Science (https://osf.io/hpy4j).

Early In-Bed Cycle Ergometry in Mechanically Ventilated Patients.

BACKGROUND: Critical illness requiring invasive mechanical ventilation can precipitate important functional disability, contributing to multidimensional morbidity following admission to an intensive care unit (ICU). Early in-bed cycle ergometry added to usual physiotherapy may mitigate ICU-acquired physical function impairment. METHODS: We randomly assigned 360 adult ICU patients undergoing invasive mechanical ventilation to receive 30 minutes of early in-bed Cycling + Usual physiotherapy (n=178) or Usual physiotherapy alone (n=182). The primary outcome was the Physical Function ICU Test-scored (PFIT-s) at 3 days after discharge from the ICU (the score ranges from 0 to 10, with higher scores indicating better function). RESULTS: Cycling began within a median (interquartile range) of 2 (1 to 3) days of starting mechanical ventilation; patients received 3 (2 to 5) cycling sessions for a mean (±standard deviation) of 27.2 ± 6.6 minutes. In both groups, patients started Usual physiotherapy within 2 (2 to 4) days of mechanical ventilation and received 4 (2 to 7) Usual physiotherapy sessions. The duration of Usual physiotherapy was 23.7 ± 15.1 minutes in the Cycling + Usual physiotherapy group and 29.1 ± 13.2 minutes in the Usual physiotherapy group. No serious adverse events occurred in either group. Among survivors, the PFIT-s at 3 days after discharge from the ICU was 7.7 ± 1.7 in the Cycling + Usual physiotherapy group and 7.5 ± 1.7 in the Usual physiotherapy group (absolute difference, 0.23 points; 95% confidence interval, -0.19 to 0.65; P=0.29). CONCLUSIONS: Among adults receiving mechanical ventilation in the ICU, adding early in-bed Cycling to usual physiotherapy did not improve physical function at 3 days after discharge from the ICU compared with Usual physiotherapy alone. Cycling did not cause any serious adverse events. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov numbers, NCT03471247 [full randomized clinical trial] and NCT02377830 [CYCLE Vanguard 46-patient internal pilot].).

Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial.

BACKGROUND: Although intravenous tranexamic acid is used in cardiac surgery to reduce bleeding and transfusion, topical tranexamic acid results in lower plasma concentrations compared with intravenous tranexamic acid, which may lower the risk of seizures. We aimed to determine whether topical tranexamic acid reduces the risk of in-hospital seizure without increasing the risk of transfusion among cardiac surgery patients. METHODS: We conducted a multicenter, double dummy, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. Between September 17, 2019, and November 28, 2023, a total of 3242 patients from 16 hospitals in 6 countries were randomly assigned (1:1 ratio) to receive either intravenous tranexamic acid (control) through surgery or topical tranexamic acid (treatment) at the end of surgery. The primary outcome was seizure, and the secondary outcome was red blood cell transfusion. After the last planned interim analysis, when 75% of anticipated participants had completed follow up, the data and safety monitoring board recommended to terminate the trial, and upon unblinding, the operations committee stopped the trial for safety. RESULTS: Among 3242 randomized patients (mean age, 66.0 years; 77.7% male), in-hospital seizure occurred in 4 of 1624 patients (0.2%) in the topical group, and 11 of 1628 patients (0.7%) in the intravenous group (absolute risk difference, -0.5% [95% CI, -0.9 to 0.03]; P=0.07). Red blood cell transfusion occurred in 570 patients (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3% [95% CI, 5.2-11.5]; P=0.007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared with the intravenous group was 8.2% (95% CI, 3.4-12.9). CONCLUSIONS: Among patients undergoing cardiac surgery, topical administration of tranexamic acid resulted in an 8.3% absolute increase in transfusion without reducing the incidence of seizure, compared with intravenous tranexamic acid. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03954314.

Reducing the burden of preventable deaths from sepsis in Canada: A need for a national sepsis action plan.

Sepsis is a global health threat with significant morbidity and mortality. Despite clinical practice guidelines and developed health systems, sepsis is often unrecognized or misdiagnosed, leading to preventable harm. In Canada, sepsis is responsible for 1 in 20 deaths and is a significant driver of health system costs. Despite being a signatory to the World Health Organization's Resolution WHA 70.7, adopted in 2017, Canada has not lived up to its commitment. Many existing sepsis policies were developed in response to a specific tragedy, and there is no national sepsis action plan. In this article, we describe the burden of sepsis, provide examples of existing, context-specific, reactionary sepsis policies, and urge a coordinated, proactive Canadian sepsis action plan to reduce the burden of sepsis.

Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis.

INTRODUCTION: Despite older adults being more vulnerable to sepsis, most preclinical research on sepsis has been conducted using young animals. This results in decreased scientific validity since age is an independent predictor of poor outcome. In this study, we explored the impact of aging on the host response to sepsis using the fecal-induced peritonitis (FIP) model developed by the National Preclinical Sepsis Platform (NPSP). METHODS: C57BL/6 mice (3 or 12 months old) were injected intraperitoneally with rat fecal slurry (0.75 mg/g) or a control vehicle. To investigate the early stage of sepsis, mice were culled at 4 h, 8 h, or 12 h to investigate disease severity, immunothrombosis biomarkers, and organ injury. Mice received buprenorphine at 4 h post-FIP. A separate cohort of FIP mice were studied for 72 h (with buprenorphine given at 4 h, 12 h, and then every 12 h post-FIP and antibiotics/fluids starting at 12 h post-FIP). Organs were harvested, plasma levels of Interleukin (IL)-6, IL-10, monocyte chemoattract protein (MCP-1)/CCL2, thrombin-antithrombin (TAT) complexes, cell-free DNA (CFDNA), and ADAMTS13 activity were quantified, and bacterial loads were measured. RESULTS: In the 12 h time course study, aged FIP mice demonstrated increased inflammation and injury to the lungs compared to young FIP mice. In the 72 h study, aged FIP mice exhibited a higher mortality rate (89%) compared to young FIP mice (42%) (p < 0.001). Aged FIP non-survivors also exhibited a trend towards elevated IL-6, TAT, CFDNA, CCL2, and decreased IL-10, and impaired bacterial clearance compared to young FIP non-survivors. CONCLUSION: To our knowledge, this is the first study to investigate the impact of age on survival using the FIP model of sepsis. Our model includes clinically-relevant supportive therapies and inclusion of both sexes. The higher mortality rate in aged mice may reflect increased inflammation and worsened organ injury in the early stage of sepsis. We also observed trends in impaired bacterial clearance, increase in IL-6, TAT, CFDNA, CCL2, and decreased IL-10 and ADAMTS13 activity in aged septic non-survivors compared to young septic non-survivors. Our aging model may help to increase the scientific validity of preclinical research and may be useful for identifying mechanisms of age-related susceptibility to sepsis as well as age-specific treatment strategies.

Sepsis and obesity: a scoping review of diet-induced obesity murine models.

BACKGROUND: Sepsis, the life-threatening host response to infection, is a major cause of mortality. Obesity increases vulnerability to sepsis; however, some degree of obesity may be protective, called the "obesity paradox". This scoping review systematically maps the literature on outcomes associated with diet-induced obesity and sepsis-induced organ injury, focusing on non-transgenic murine models. METHODS: A literature search of primary articles was conducted from database inception to June 2023. Eligible articles compared diet-induced obesity to non-obese mice in sepsis models involving live pathogens. Two reviewers screened articles and extracted data on obesogenic and sepsis models utilized, and organ injury outcomes, including physiological dysfunction, histological alterations, and biochemical changes. RESULTS: Seventeen studies met eligibility criteria; 82% used male C57BL/6 mice, and 88% used cecal ligation and puncture to induce sepsis. Most studies used 60% high-fat diets compared to 10-16% fat in controls. Seven (64%) studies reported increased mortality in obese septic mice, one (9%) observed a decrease, and three (37%) found no significant difference. The liver, lungs, and kidneys were the most studied organs. Alanine transaminase results were inconclusive. Myeloperoxidase levels were increased in the livers of two studies and inconclusive in the lungs of obese septic mice. Creatinine and neutrophil gelatinase-associated lipocalin were elevated in obese septic mice. CONCLUSIONS: There is variability in the methodology and measured outcomes in murine models of diet-induced obesity and sepsis and a lack of studies in female mice. The absence of standardized models has produced conflicting findings on the impact of obesity on sepsis outcomes.

Sepsis policy, guidelines and standards in Canada: a jurisdictional scoping review protocol.

INTRODUCTION: To our knowledge, this study is the first to identify and describe current sepsis policies, clinical practice guidelines, and health professional training standards in Canada to inform evidence-based policy recommendations. METHODS AND ANALYSIS: This study will be designed and reported according to the Arksey and O'Malley framework for scoping reviews and the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews. EMBASE, CINAHL, Medline, Turning Research Into Practice and Policy Commons will be searched for policies, clinical practice guidelines and health professional training standards published or updated in 2010 onwards, and related to the identification, management or reporting of sepsis in Canada. Additional sources of evidence will be identified by searching the websites of Canadian organisations responsible for regulating the training of healthcare professionals and reporting health outcomes. All potentially eligible sources of evidence will be reviewed for inclusion, followed by data extraction, independently and in duplicate. The included policies will be collated and summarised to inform future evidence-based sepsis policy recommendations. ETHICS AND DISSEMINATION: The proposed study does not require ethics approval. The results of the study will be submitted for publication in a peer-reviewed journal and presented at local, national and international forums.

Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU: 2023.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care hospitals have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes (PICO) format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation Approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among unselected patients. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system. CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Executive Summary: Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care facilities have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based clinical practice guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among "unselected" patients due to the absence of data regarding the benefit and the potential harms of false positive alarms, the risk of alarm fatigue, and cost. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system (GPS). CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

REVIEWING THE DYSREGULATION OF ADAMTS13 AND VWF IN SEPSIS.

ABSTRACT: Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the intensive care unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation, which is characterized by microvascular thrombosis. Von Willebrand factor (VWF) and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of VWF and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their use as markers of severe illness, and potential targets for new therapeutic development.

A Hospital-Wide Open-Label Cluster Crossover Pragmatic Comparative Effectiveness Randomized Trial Comparing Normal Saline to Ringer's Lactate: Protocol and Statistical Analysis Plan of The FLUID Trial.

BACKGROUND: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids given to hospitalized patients. Despite concern about possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function, and death), few large multicenter randomized trials focused on critically ill patients have compared these fluids. Uncertainty exists about the effects of these fluids on clinically important outcomes across all hospitalized patients. OBJECTIVE: The FLUID trial is a pragmatic, multicenter, 2×2 cluster crossover comparative effectiveness randomized trial that aims to evaluate the effectiveness of a hospital-wide policy that stocks either NS or RL as the main crystalloid fluid in 16 hospitals across Ontario, Canada. METHODS: All hospitalized adult and pediatric patients (anticipated sample size 144,000 patients) with an incident admission to the hospital over the course of each study period will be included. Either NS or RL will be preferentially stocked throughout the hospital for 12 weeks before crossing to the alternate fluid for the subsequent 12 weeks. The primary outcome is a composite of death and hospital readmission within 90 days of hospitalization. Secondary outcomes include death, hospital readmission, dialysis, reoperation, postoperative reintubation, length of hospital stay, emergency department visits, and discharge to a facility other than home. All outcomes will be obtained from health administrative data, eliminating the need for individual case reports. The primary analysis will use cluster-level summaries to estimate cluster-average treatment effects. RESULTS: The statistical analysis plan has been prepared "a priori" in advance of receipt of the trial data set from ICES and any analyses. CONCLUSIONS: We describe the protocol and statistical analysis plan for the evaluation of primary and secondary outcomes for the FLUID trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04512950; https://classic.clinicaltrials.gov/ct2/show/NCT04512950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51783.