Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

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

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

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.

Clinical Practice Guideline Recommendations in Pediatric Mild Traumatic Brain Injury: A Systematic Review.

STUDY OBJECTIVE: Our primary objectives were to identify clinical practice guideline recommendations for children with acute mild traumatic brain injury (mTBI) presenting to an emergency department (ED), appraise their overall quality, and synthesize the quality of evidence and the strength of included recommendations. METHODS: We searched MEDLINE, EMBASE, Cochrane Central, Web of Science, and medical association websites from January 2012 to May 2023 for clinical practice guidelines with at least 1 recommendation targeting pediatric mTBI populations presenting to the ED within 48 hours of injury for any diagnostic or therapeutic intervention in the acute phase of care (ED and inhospital). Pairs of reviewers independently assessed overall clinical practice guideline quality using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The quality of evidence on recommendations was synthesized using a matrix based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Evidence-to-Decision framework. RESULTS: We included 11 clinical practice guidelines, of which 6 (55%) were rated high quality. These included 101 recommendations, of which 34 (34%) were based on moderate- to high-quality evidence, covering initial assessment, initial diagnostic imaging, monitoring/observation, therapeutic interventions, discharge advice, follow-up, and patient and family support. We did not identify any evidence-based recommendations in high-quality clinical practice guidelines for repeat imaging, neurosurgical consultation, or hospital admission. Lack of strategies and tools to aid implementation and editorial independence were the most common methodological weaknesses. CONCLUSIONS: We identified 34 recommendations based on moderate- to high-quality evidence that may be considered for implementation in clinical settings. Our review highlights important areas for future research. This review also underlines the importance of providing strategies to facilitate the implementation of clinical practice guideline recommendations for pediatric mTBI.

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.

Implementation of an audit and feedback module targeting low-value clinical practices in a provincial trauma quality assurance program: a cost-effectiveness study.

BACKGROUND: Audit and Feedback (A&F) interventions based on quality indicators have been shown to lead to significant improvements in compliance with evidence-based care including de-adoption of low-value practices (LVPs). Our primary aim was to evaluate the cost-effectiveness of adding a hypothetical A&F module targeting LVPs for trauma admissions to an existing quality assurance intervention targeting high-value care and risk-adjusted outcomes. A secondary aim was to assess how certain A&F characteristics might influence its cost-effectiveness. METHODS: We conducted a cost-effectiveness analysis using a probabilistic static decision analytic model in the Québec trauma care continuum. We considered the Québec Ministry of Health perspective. Our economic evaluation compared a hypothetical scenario in which the A&F module targeting LVPs is implemented in a Canadian provincial trauma quality assurance program to a status quo scenario in which the A&F module is not implemented. In scenarios analyses we assessed the impact of A&F characteristics on its cost-effectiveness. Results are presented in terms of incremental costs per LVP avoided. RESULTS: Results suggest that the implementation of A&F module (Cost = $1,480,850; Number of LVPs = 6,005) is associated with higher costs and higher effectiveness compared to status quo (Cost = $1,124,661; Number of LVPs = 8,228). The A&F module would cost $160 per LVP avoided compared to status quo. The A&F module becomes more cost-effective with the addition of facilitation visits; more frequent evaluation; and when only high-volume trauma centers are considered. CONCLUSION: A&F module targeting LVPs is associated with higher costs and higher effectiveness than status quo and has the potential to be cost-effective if the decision-makers' willingness-to-pay is at least $160 per LVP avoided. This likely represents an underestimate of true ICER due to underestimated costs or missed opportunity costs. Results suggest that virtual facilitation visits, frequent evaluation, and implementing the module in high-volume centers can improve cost-effectiveness.

Impact of Early Tracheostomy Versus Late or No Tracheostomy in Nonneurologically Injured Adult Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: The optimal timing of tracheostomy in nonneurologically injured mechanically ventilated critically ill adult patients is uncertain. We conducted a systematic review of randomized controlled trials to evaluate the effect of early versus late tracheostomy or prolonged intubation in this population. DATA SOURCES: We searched MEDLINE, Embase, CENTRAL, CINAHL, and Web of science databases for randomized controlled trials comparing early tracheostomy (<10 d of intubation) with late tracheostomy or prolonged intubation in adults. DATA SELECTION: We selected trials comparing early tracheostomy (defined as being performed less than 10 d after intubation) with late tracheostomy (performed on or after the 10th day of intubation) or prolonged intubation and no tracheostomy in nonneurologically injured patients. The primary outcome was overall mortality. Secondary outcomes included ventilator-associated pneumonia, duration of mechanical ventilation, ICU, and hospital length of stay. DATA EXTRACTION: Two reviewers screened citations, extracted data, assessed the risk of bias, and classification of Grading of Recommendations, Assessment, Development, and Evaluation independently. DATA SYNTHESIS: Our search strategy yielded 8,275 citations, from which nine trials (n = 2,457) were included. We did not observe an effect on the overall mortality of early tracheostomy compared with late tracheostomy or prolonged intubation (risk ratio, 0.91, 95% CI, 0.82-1.01; I2 = 18%). Our results were consistent in all subgroup analyses. No differences were observed in ICU and hospital length of stay, duration of mechanical ventilation, incidence of ventilator-acquired pneumonia, and complications. Our trial sequential analysis showed that our primary analysis on mortality was likely underpowered. CONCLUSION: In our systematic review, we observed that early tracheostomy, as compared with late tracheostomy or prolonged intubation, was not associated with a reduction in overall mortality. However, we cannot exclude a clinically relevant reduction in mortality considering the level of certainty of the evidence. A well-designed trial is needed to answer this important clinical question.

Interdisciplinary strategies to prevent long-term and detrimental opioid use following trauma: a stakeholder consensus study.

OBJECTIVE: Prolonged opioid use is common following traumatic injuries. Although preventive strategies have been recommended, the evidence supporting their use is low. The objectives of this study were to select interdisciplinary strategies to prevent long-term, detrimental opioid use in trauma patients for further evaluation and to identify implementation considerations. DESIGN: A consensus study using the nominal group technique. SETTING: Four trauma systems in Canada. SUBJECTS: Participants included expert clinicians and decision makers, and people with lived experience. METHODS: Participants had to discuss the relevance and implementation of 15 strategies and then rank them using a 7-point Likert scale. Implementation considerations were identified through a synthesis of discussions. RESULTS: A total of 41 expert stakeholders formed the nominal groups. Overall, eight strategies were favored: 1) using multimodal approach for pain management, 2) professional follow-up in physical health, 3) assessment of risk factors for opioid misuse, 4) physical stimulation, 5) downward adjustment of opioids based on patient recovery, 6) educational intervention for patients, 7) training offered to professionals on how to prescribe opioids, and 8) optimizing communication between professionals working in different settings. Discussions with expert stakeholders revealed the rationale for the selected strategies and identified issues to consider when implementing them. CONCLUSION: This stakeholder consensus study identified, for further scientific study, a set of interdisciplinary strategies to promote appropriate opioid use following traumatic injuries. These strategies could ultimately decrease the burden associated with long-term opioid use.

Tracheostomy versus prolonged intubation in moderate to severe traumatic brain injury: a multicentre retrospective cohort study.

PURPOSE: Tracheostomy is a surgical procedure that is commonly performed in patients admitted to the intensive care unit (ICU). It is frequently required in patients with moderate to severe traumatic brain injury (TBI), a subset of patients with prolonged altered state of consciousness that may require a long period of mechanical respiratory assistance. While many clinicians favour the use of early tracheostomy in TBI patients, the evidence in favour of this practice remains scarce. The aims of our study were to evaluate the potential clinical benefits of tracheostomy versus prolonged endotracheal intubation, as well as whether the timing of the procedure may influence outcome in patients with moderate to severe TBI. METHODS: We conducted a retrospective multicentre cohort study based on data from the provincial integrated trauma system of Quebec (Québec Trauma Registry). The study population was selected from adult trauma patients hospitalized between 2013 and 2019. We included patients 16 yr and older with moderate to severe TBI (Glasgow Coma Scale score < 13) who required mechanical ventilation for 96 hr or longer. Our primary outcome was 30-day mortality. Secondary outcomes included hospital and ICU mortality, six-month mortality, duration of mechanical ventilation, ventilator-associated pneumonia, ICU and hospital length of stay as well as orientation of patients upon discharge from the hospital. We used propensity score covariate adjustment. To overcome the effect of immortal time bias, an extended Cox shared frailty model was used to compare mortality between groups. RESULTS: From 2013 to 2019, 26,923 patients with TBI were registered in the Québec Trauma Registry. A total of 983 patients who required prolonged endotracheal intubation for 96 hr or more were included in the study, 374 of whom underwent a tracheostomy and 609 of whom remained intubated. We observed a reduction in 30-day mortality (adjusted hazard ratio, 0.33; 95% confidence interval, 0.21 to 0.53) associated with tracheostomy compared with prolonged endotracheal intubation. This effect was also seen in the ICU as well as at six months. Tracheostomy, when compared with prolonged endotracheal intubation, was associated with an increase in the duration of mechanical respiratory assistance without any increase in the length of stay. No effect on mortality was observed when comparing early vs late tracheostomy procedures. An early procedure was associated with a reduction in the duration of mechanical respiratory support as well as hospital and ICU length of stay. CONCLUSION: In this multicentre cohort study, tracheostomy was associated with decreased mortality when compared with prolonged endotracheal intubation in patients with moderate to severe TBI. This effect does not appear to be modified by the timing of the procedure. Nevertheless, the generalization and application of these results remains limited by potential residual time-dependent indication bias.

RéSUMé: INTRODUCTION: La trachéotomie est une intervention chirurgicale communément pratiquée chez les personnes admises à l'unité de soins intensifs (USI). Elle est fréquemment requise chez les patient·es victimes d'un traumatisme craniocérébral (TCC) modéré à grave, un sous-groupe présentant une altération prolongée de l'état de conscience qui peut nécessiter une longue période d'assistance respiratoire mécanique. Bien que bon nombre de cliniciens et cliniciennes soient favorables à l'utilisation d'une trachéotomie précoce chez cette patientèle, les données probantes en faveur de cette pratique restent insuffisantes. Les objectifs de notre étude étaient d'évaluer l'effet de la trachéotomie par rapport à l'intubation endotrachéale prolongée, ainsi que si le moment où la procédure est effectuée pouvait influencer cet effet, chez les personnes ayant subi un TCC modéré à grave. MéTHODES: Nous avons effectué une étude de cohorte rétrospective multicentrique basée sur le système provincial intégré de traumatologie du Québec (Registre des traumatismes du Québec). La population de l'étude a été sélectionnée parmi les patient·es adultes victimes de traumatismes hospitalisé·es entre 2013 et 2019. Nous avons inclus les patient·es âgé·es de 16 ans et plus présentant un TCC modéré à grave (score sur l'échelle de coma de Glasgow [GCS] < 13) ayant nécessité une assistance respiratoire mécanique pendant 96 h ou plus. Notre critère d'évaluation principal était la mortalité à 30 jours. Les critères d'évaluation secondaires comprenaient la mortalité hospitalière et à l'USI, la mortalité à 6 mois, la durée d'assistance respiratoire mécanique, les pneumonies acquises en lien avec l'assistance respiratoire mécanique, les durées de séjour à l'USI et à l'hôpital ainsi que l'orientation des patient·es à leur sortie de l'hôpital. Nous avons utilisé un score de propension pour l'ajustement des covariables. Pour corriger l'effet du biais du temps immortel, un modèle de régression de la fragilité partagée de Cox étendu a été utilisé pour estimer la mortalité entre les groupes. RéSULTATS: De 2013 à 2019, 26 923 personnes victimes de TCC ont été inscrites dans le Registre des traumatismes du Québec. Un total de 983 patient·es ayant nécessité une intubation endotrachéale prolongée de 96 h ou plus ont été inclus·es dans l'étude, dont 374 ont subi une trachéotomie et 609 sont resté·es intubé·es. Nous avons observé une réduction de la mortalité à 30 jours (aHR : 0,33 [0,21 − 0,53]) associée à la trachéotomie en comparaison à l'intubation endotrachéale prolongée. Cet effet a également été observé à l'USI ainsi qu'à 6 mois. La trachéotomie, comparée à l'intubation endotrachéale prolongée, était associée à une augmentation de la durée d'assistance respiratoire mécanique sans augmentation de la durée de séjour. Aucun effet sur la mortalité n'a été observé en comparant les procédures de trachéotomie précoces et tardive. Une procédure précoce a été associée à une réduction de la durée d'assistance respiratoire mécanique ainsi que la durée de séjour à l'USI et à l'hôpital. CONCLUSION: Dans cette étude de cohorte multicentrique, nous avons observé que la trachéotomie est associée à une diminution de la mortalité en comparaison à l'intubation endotrachéale prolongée chez la patientèle ayant subi un TCC modéré ou grave. Cet effet ne semble pas modifié par le moment de la procédure durant l'hospitalisation. La généralisation et l'application de ces résultats restent toutefois limitées par un biais d'indication résiduel potentiel.

Diagnostic accuracy of ancillary tests for death by neurologic criteria: a systematic review and meta-analysis.

PURPOSE: Ancillary tests are frequently used in death determination by neurologic criteria (DNC), particularly when the clinical neurologic examination is unreliable. Nevertheless, their diagnostic accuracy has not been extensively studied. Our objective was to synthesize the sensitivity and specificity of commonly used ancillary tests for DNC. SOURCE: We performed a systematic review and meta-analysis by searching MEDLINE, EMBASE, Cochrane databases, and CINAHL Ebsco from their inception to 4 February 2022. We selected cohort and case-control studies including patients with 1) clinically diagnosed death by neurologic criteria or 2) clinically suspected death by neurologic criteria who underwent ancillary testing for DNC. We excluded studies without a priori diagnostic criteria and studies conducted solely on pediatric patients. Accepted reference standards were clinical examination, four-vessel conventional angiography, and radionuclide imaging. Data were directly extracted from published reports. We assessed the methodological quality of studies with the QUADAS-2 tool and estimated ancillary test sensitivities and specificities using hierarchical Bayesian models with diffuse priors. PRINCIPAL FINDINGS: Overall, 137 records met the selection criteria. One study (0.7%) had a low risk of bias in all QUADAS-2 domains. Among clinically diagnosed death by neurologic criteria patients (n = 8,891), ancillary tests had similar pooled sensitivities (range, 0.82-0.93). Sensitivity heterogeneity was greater within (σ = 0.10-0.15) than between (σ = 0.04) ancillary test types. Among clinically suspected death by neurologic criteria patients (n = 2,732), pooled ancillary test sensitivities ranged between 0.81 and 1.00 and specificities between 0.87 and 1.00. Most estimates had high statistical uncertainty. CONCLUSION: Studies assessing ancillary test diagnostic accuracy have an unclear or high risk of bias. High-quality studies are required to thoroughly validate ancillary tests for DNC. STUDY REGISTRATION: PROSPERO (CRD42013005907); registered 7 October 2013.

RéSUMé: OBJECTIF: Les examens auxiliaires sont fréquemment utilisés dans la détermination du décès selon des critères neurologiques (DCN), en particulier lorsque l'examen neurologique clinique n'est pas fiable. Néanmoins, leur précision diagnostique n'a pas été étudiée de manière approfondie. Notre objectif était de synthétiser la sensibilité et la spécificité des examens auxiliaires couramment utilisés pour la DCN. SOURCES: Nous avons réalisé une revue systématique et une méta-analyse en effectuant des recherches dans les bases de données MEDLINE, EMBASE, Cochrane et CINAHL Ebsco de leur création jusqu'au 4 février 2022. Nous avons sélectionné des études de cohorte et cas témoins incluant des patients présentant 1) un décès selon des critères neurologiques diagnostiqué cliniquement ou 2) un décès selon des critères neurologiques soupçonné cliniquement qui ont été soumis à des examens auxiliaires pour un DCN. Nous avons exclu les études sans critères diagnostiques a priori et les études menées uniquement auprès de patients pédiatriques. Les normes de référence acceptées étaient l'examen clinique, l'angiographie conventionnelle à quatre vaisseaux et l'imagerie nucléaire. Les données ont été directement extraites de comptes rendus publiés. Nous avons évalué la qualité méthodologique des études avec l'outil QUADAS-2 et estimé les sensibilités et les spécificités des examens auxiliaires à l'aide de modèles hiérarchiques bayésiens avec des distributions préalables diffuses. CONSTATATIONS PRINCIPALES: Au total, 137 études répondaient aux critères de sélection. Une étude (0,7 %) présentait un faible risque de biais dans tous les domaines de QUADAS-2. Parmi les patients ayant reçu un diagnostic clinique de décès selon des critères neurologiques (n = 8891), les examens auxiliaires présentaient des sensibilités combinées similaires (intervalle de 0,82 à 0,93). L'hétérogénéité de sensibilité était plus grande au sein (σ = 0,10-0,15) plutôt qu'entre (σ = 0,04) les types d'examens auxiliaires. Parmi les patients cliniquement soupçonnés de décès selon des critères neurologiques (n = 2732), les sensibilités combinées des examens auxiliaires variaient entre 0,81 et 1,00 et les spécificités entre 0,87 et 1,00. La plupart des estimations comportaient une grande incertitude statistique. CONCLUSION: Les études évaluant la précision diagnostique des examens auxiliaires présentent un risque de biais incertain ou élevé. Des études de haute qualité sont nécessaires pour valider en profondeur les examens auxiliaires pour la DCN. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42013005907); enregistrée le 7 octobre 2013.

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.

Strategies to prevent long-term opioid use following trauma: a Canadian practice survey.

PURPOSE: To evaluate how Canadian clinicians involved in trauma patient care and prescribing opioids perceive the use and effectiveness of strategies to prevent long-term opioid therapy following trauma. Barriers and facilitators to the implementation of these strategies were also assessed. METHODS: We conducted a web-based cross-sectional survey. Potential participants were identified by trauma program managers and directors of the targeted departments in three Canadian provinces. We designed our questionnaire using standard health survey research methods. The questionnaire was administered between April 2021 and November 2021. RESULTS: Our response rate was 47% (350/744), and 52% (181/350) of participants completed the entire survey. Most respondents (71%, 129/181) worked in teaching hospitals. Multimodal analgesia (93%, 240/257), nonsteroidal anti-inflammatory agents (77%, 198/257), and physical stimulation (75%, 193/257) were the strategies perceived to be the most frequently used. Several preventive strategies were perceived to be very effective by over 80% of respondents. Of these, some that were reported as not being frequently used were perceived to be among the most effective ones, including guidelines or protocols, assessing risk factors for opioid misuse, physical health follow-up by a professional, training for clinicians, patient education, and prescription monitoring systems. Staff shortages, time constraints, and organizational practices were identified as the main barriers to the implementation of the highest ranked preventive strategies. CONCLUSIONS: Several strategies to prevent long-term opioid therapy following trauma are perceived as being effective by those prescribing opioids in this population. Some of these strategies appear to be commonly used in everyday practice and others less so. Future research should focus on which preventive strategies should be given higher priority for implementation before assessing their effectiveness.

RéSUMé: OBJECTIF: Évaluer comment les cliniciens canadiens impliqués dans les soins aux patients traumatisés et prescrivant des opioïdes perçoivent l'utilisation et l'efficacité des stratégies visant à prévenir le traitement prolongé par opioïde après un traumatisme. Les obstacles et facilitateurs de la mise en œuvre de ces stratégies ont aussi été analysés. MéTHODES: Nous avons réalisé une enquête transversale via le Web. Les participants potentiels ont été identifiés par les gestionnaires et directeurs de programmes de traumatologie des départements ciblés dans trois provinces canadiennes. Nous avons conçu notre questionnaire en utilisant la méthodologie de recherche usuelle des enquêtes de santé. Le questionnaire a été administré entre avril 2021 et novembre 2021. RéSULTATS: Notre taux de réponse a été de 47 % (350/744) et 52 % (181/350) des participants ont complété l'enquête dans sa totalité. La majorité des personnes interrogées (71 %, 129/181) travaillait dans des hôpitaux universitaires. L'analgésie multimodale (93 %, 240/257), les anti-inflammatoires non stéroïdiens (77 %, 198/257) et la stimulation physique (75 %, 193/257) étaient les stratégies perçues comme étant le plus fréquemment utilisées. Plusieurs stratégies préventives étaient perçues comme étant très efficaces par plus de 80 % des répondants. Parmi celles-ci, certaines étaient signalées comme n'étant pas utilisées très souvent, mais perçues comme étant les plus efficaces, notamment les lignes directrices et protocoles évaluant les facteurs de risque d'utilisation abusive des opioïdes, le suivi de la santé physique par un professionnel, la formation des cliniciens, l'éducation des patients et les systèmes de suivi des prescriptions. La pénurie de personnels, les contraintes de temps et les pratiques de l'établissement ont été identifiées comme étant les principaux obstacles à la mise en place des stratégies préventives classées parmi les premières. CONCLUSIONS: Plusieurs stratégies de prévention du traitement par opioïdes à long terme après un traumatisme sont perçues comme efficaces par ceux qui les prescrivent à cette population de patients. Certaines de ces stratégies apparaissent comme couramment utilisées dans la pratique quotidienne et d'autres moins souvent. La recherche future devrait se concentrer sur la détermination des stratégies préventives auxquelles il faudrait accorder la plus grande priorité de mise en œuvre avant d'évaluer leur efficacité.

Clinical Practice Guideline Recommendations in Pediatric Orthopaedic Injury: A Systematic Review.

BACKGROUND: Lack of adherence to recommendations on pediatric orthopaedic injury care may be driven by lack of knowledge of clinical practice guidelines (CPGs), heterogeneity in recommendations or concerns about their quality. We aimed to identify CPGs for pediatric orthopaedic injury care, appraise their quality, and synthesize the quality of evidence and the strength of associated recommendations. METHODS: We searched Medline, Embase, Cochrane CENTRAL, Web of Science and websites of clinical organizations. CPGs including at least one recommendation targeting pediatric orthopaedic injury populations on any diagnostic or therapeutic intervention developed in the last 15 years were eligible. Pairs of reviewers independently extracted data and evaluated CPG quality using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. We synthesized recommendations from high-quality CPGs using a recommendations matrix based on the GRADE Evidence-to-Decision framework. RESULTS: We included 13 eligible CPGs, of which 7 were rated high quality. Lack of stakeholder involvement and applicability (i.e., implementation strategies) were identified as weaknesses. We extracted 53 recommendations of which 19 were based on moderate or high-quality evidence. CONCLUSIONS: We provide a synthesis of recommendations from high-quality CPGs that can be used by clinicians to guide treatment decisions. Future CPGs should aim to use a partnership approach with all key stakeholders and provide strategies to facilitate implementation. This study also highlights the need for more rigorous research on pediatric orthopaedic trauma. LEVEL OF EVIDENCE: Level II-therapeutic study.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Association of age with death and withdrawal of life-sustaining therapy after severe traumatic brain injury.

BACKGROUND: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention. METHODS: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy. RESULTS: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions. CONCLUSION: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear.

Interhospital Variations in Resource Use Intensity for In-hospital Injury Deaths: A Retrospective Multicenter Cohort Study.

OBJECTIVE: Evaluate interhospital variation in resource use for in-hospital injury deaths. BACKGROUND: Significant variation in resource use for end-of-life care has been observed in the US for chronic diseases. However, there is an important knowledge gap on end-of-life resource use for trauma patients. METHODS: We conducted a multicenter, retrospective cohort study of injury deaths following hospitalization in any of the 57 trauma centers in a Canadian trauma system (2013-2016). Resource use intensity was measured using activity-based costing (2016 $CAN) according to time of death (72 h, 3-14 d, ≥14 d). We used multilevel log-linear regression to model resource use and estimated interhospital variation using intraclass correlation coefficients (ICC). RESULTS: Our study population comprised 2044 injury deaths. Variation in resource use between hospitals was observed for all 3 time frames (ICC = 6.5%, 6.6%, and 5.9% for < 72 h, 3-14 d, and ≥14 d, respectively). Interhospital variation was stronger for allied health services (ICC = 18 to 26%), medical imaging (ICC = 4 to 10%), and the ICU (ICC = 5 to 6%) than other activity centers. We observed stronger interhospital variation for patients < 65 years of age (ICC = 11 to 34%) than those ≥65 (ICC = 5 to 6%) and for traumatic brain injury (ICC = 5 to 13%) than other injuries (ICC = 1 to 8%). CONCLUSIONS: We observed variation in resource use intensity for injury deaths across trauma centers. Strongest variation was observed for younger patients and those with traumatic brain injury. Results may reflect variation in level of care decisions and the incidence of withdrawal of life-sustaining therapies.

Probiotics in Critical Illness: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To determine the safety and efficacy of probiotics or synbiotics on morbidity and mortality in critically ill adults and children. DATA SOURCES: We searched MEDLINE, EMBASE, CENTRAL, and unpublished sources from inception to May 4, 2021. STUDY SELECTION: We performed a systematic search for randomized controlled trials (RCTs) that compared enteral probiotics or synbiotics to placebo or no treatment in critically ill patients. We screened studies independently and in duplicate. DATA EXTRACTION: Independent reviewers extracted data in duplicate. A random-effects model was used to pool data. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: Sixty-five RCTs enrolled 8,483 patients. Probiotics may reduce ventilator-associated pneumonia (VAP) (relative risk [RR], 0.72; 95% CI, 0.59 to 0.89 and risk difference [RD], 6.9% reduction; 95% CI, 2.7-10.2% fewer; low certainty), healthcare-associated pneumonia (HAP) (RR, 0.70; 95% CI, 0.55-0.89; RD, 5.5% reduction; 95% CI, 8.2-2.0% fewer; low certainty), ICU length of stay (LOS) (mean difference [MD], 1.38 days fewer; 95% CI, 0.57-2.19 d fewer; low certainty), hospital LOS (MD, 2.21 d fewer; 95% CI, 1.18-3.24 d fewer; low certainty), and duration of invasive mechanical ventilation (MD, 2.53 d fewer; 95% CI, 1.31-3.74 d fewer; low certainty). Probiotics probably have no effect on mortality (RR, 0.95; 95% CI, 0.87-1.04 and RD, 1.1% reduction; 95% CI, 2.8% reduction to 0.8% increase; moderate certainty). Post hoc sensitivity analyses without high risk of bias studies negated the effect of probiotics on VAP, HAP, and hospital LOS. CONCLUSIONS: Low certainty RCT evidence suggests that probiotics or synbiotics during critical illness may reduce VAP, HAP, ICU and hospital LOS but probably have no effect on mortality.

Economic Evaluation of In-Hospital Clinical Practices in Acute Injury Care: A Systematic Review.

OBJECTIVES: Underuse of high-value clinical practices and overuse of low-value practices are major sources of inefficiencies in modern healthcare systems. To achieve value-based care, guidelines and recommendations should target both underuse and overuse and be supported by evidence from economic evaluations. We aimed to conduct a systematic review of the economic value of in-hospital clinical practices in acute injury care to advance knowledge on value-based care in this patient population. METHODS: Pairs of independent reviewers systematically searched MEDLINE, Embase, Web of Science, and Cochrane Central Register for full economic evaluations of in-hospital clinical practices in acute trauma care published from 2009 to 2019 (last updated on June 17, 2020). Results were converted into incremental net monetary benefit and were summarized with forest plots. The protocol was registered with PROSPERO (CRD42020164494). RESULTS: Of 33 910 unique citations, 75 studies met our inclusion criteria. We identified 62 cost-utility, 8 cost-effectiveness, and 5 cost-minimization studies. Values of incremental net monetary benefit ranged from international dollars -467 000 to international dollars 194 000. Of 114 clinical interventions evaluated (vs comparators), 56 were cost-effective. We identified 15 cost-effective interventions in emergency medicine, 6 in critical care medicine, and 35 in orthopedic medicine. A total of 58 studies were classified as high quality and 17 as moderate quality. From studies with a high level of evidence (randomized controlled trials), 4 interventions were clearly dominant and 8 were dominated. CONCLUSIONS: This research advances knowledge on value-based care for injury admissions. Results suggest that almost half of clinical interventions in acute injury care that have been studied may not be cost-effective.

Clinical evaluation and ancillary testing for the diagnosis of death by neurologic criteria: a cross-sectional survey of Canadian intensivists.

PURPOSE: Trust in the deceased organ donation process relies on the expectation that the diagnosis of death by neurologic criteria (DNC) is accurate and reliable. The objective of this study was to assess the perceptions and approaches to DNC diagnosis among Canadian intensivists. METHODS: We conducted a self-administered, online, cross-sectional survey of Canadian intensivists. Our sampling frame included all intensivists practicing in Canadian institutions. Results are reported using descriptive statistics. RESULTS: Among 550 identified intensivists, 249 (45%) completed the survey. Respondents indicated they would be comfortable diagnosing DNC based on clinical criteria alone in cases where there is movement in response to stimulation (119/248; 48%); inability to evaluate upper/lower extremity responses (84/249; 34%); spontaneous peripheral movement (76/249; 31%); inability to evaluate both oculocephalic and oculo-caloric reflexes (40/249; 16%); presence of high cervical spinal cord injury (40/249; 16%); and within 24 hr of hypoxemic-ischemic brain injury (38/247; 15%). Most respondents agreed that an ancillary test should always be conducted when a complete clinical evaluation is impossible (225/241; 93%); when there is possibility of a residual sedative effect (216/242; 89%); when the mechanism for brain injury is unclear (172/241; 71%); and if isolated brainstem injury is suspected (142/242; 59%). Sixty-six percent (158/241) believed that ancillary tests are sensitive and 55% (132/241) that they are specific for DNC. Respondents considered the following ancillary tests useful for DNC: four-vessel conventional angiography (211/241; 88%), nuclear imaging (179/240; 75%), computed tomography (CT) angiography (156/240; 65%), and CT perfusion (134/240; 56%). CONCLUSION: There is variability in perceptions and approaches to DNC diagnosis among Canadian intensivists, and some practices are inconsistent with national recommendations.

RéSUMé: OBJECTIF: La confiance dans le processus de don d'organes de donneurs décédés repose sur l'attente que le diagnostic de décès déterminé par des critères neurologiques (DDN) soit précis et fiable. L'objectif de cette étude était d'évaluer les perceptions et les approches du diagnostic de DDN chez les intensivistes canadiens. MéTHODE: Nous avons mené un sondage transversal auto-administré et en ligne auprès des intensivistes canadiens. Notre base d'échantillonnage comprenait tous les intensivistes exerçant dans des établissements canadiens. Les résultats sont présentés à l'aide de statistiques descriptives. RéSULTATS: Parmi les 550 intensivistes identifiés, 249 (45 %) ont répondu au sondage. Les répondants ont indiqué qu'ils seraient à l'aise de diagnostiquer un DDN en fonction de critères cliniques seulement dans les cas où il y a : un mouvement en réponse à une stimulation (119/248; 48 %); une incapacité à évaluer les réponses des membres supérieurs et inférieurs (84/249; 34 %); un mouvement périphérique spontané (76/249; 31 %); une incapacité à évaluer à la fois les réflexes oculo-céphaliques et vestibulo-oculaires (40/249; 16 %); la présence de lésions médullaires cervicales hautes (40/249; 16 %); et dans les 24 heures suivant une lésion cérébrale hypoxémique-ischémique (38/247; 15 %). La plupart des répondants étaient d'accord pour dire qu'un test auxiliaire devrait toujours être réalisé lorsqu'une évaluation clinique complète est impossible (225/241; 93 %); lorsqu'il y a possibilité d'un effet sédatif résiduel (216/242; 89 %); lorsque le mécanisme de la lésion cérébrale n'est pas clair (172/241; 71 %); et si une lésion isolée du tronc cérébral est suspectée (142/242; 59 %). Soixante-six pour cent (158/241) des répondants étaient d'avis que les tests auxiliaires étaient sensibles et 55 % (132/241) qu'ils étaient spécifiques pour le DDN. Les répondants ont jugé utiles les tests auxiliaires suivants pour le DDN : l'angiographie conventionnelle des quatre vaisseaux (211/241; 88 %), l'imagerie nucléaire (179/240; 75 %), l'angiographie par tomodensitométrie (TDM) (156/240; 65 %) et la perfusion en TDM (134/240; 56 %). CONCLUSION: Les perceptions et les approches du diagnostic de DDN varient parmi les intensivistes canadiens, et certaines pratiques ne sont pas conformes aux recommandations nationales.

Health economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): a cost-effectiveness analysis.

PURPOSE: We sought to compare the cost-effectiveness of probiotics and usual care with usual care without probiotics in mechanically ventilated, intensive care unit patients alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT). METHODS: We conducted a health economic evaluation alongside the PROSPECT randomized control trial (October 2013-March 2019). We adopted a public healthcare payer's perspective. Forty-four intensive care units in three countries (Canada/USA/Saudi Arabia) with adult critically ill, mechanically ventilated patients (N = 2,650) were included. Interventions were probiotics (Lactobacillus rhamnosus GG) vs placebo administered enterally twice daily. We collected healthcare resource use and estimated unit costs in 2019 United States dollars (USD) over a time horizon from randomization to hospital discharge/death. We calculated incremental cost-effectiveness ratios (ICERs) comparing probiotics vs usual care. The primary outcome was incremental cost per ventilator-associated pneumonia (VAP) event averted; secondary outcomes were costs per Clostridioides difficile-associated diarrhea (CDAD), antibiotic-associated diarrhea (AAD), and mortality averted. Uncertainty was investigated using nonparametric bootstrapping and sensitivity analyses. RESULTS: Mean (standard deviation [SD]) cost per patient was USD 66,914 (91,098) for patients randomized to probiotics, with a median [interquartile range (IQR)] of USD 42,947 [22,239 to 76,205]. By comparison, for those not receiving probiotics, mean (SD) cost per patient was USD 62,701 (78,676) (median [IQR], USD 41,102 [23,170 to 75,140]; incremental cost, USD 4,213; 95% confidence interval [CI], -2,269 to 10,708). Incremental cost-effectiveness ratios for VAP or AAD events averted, probiotics were dominated by usual care (more expensive, with similar effectiveness). The ICERs were USD 1,473,400 per CDAD event averted (95% CI, undefined) and USD 396,764 per death averted (95% CI, undefined). Cost-effectiveness acceptability curves reveal that probiotics were not cost-effective across wide ranges of plausible willingness-to-pay thresholds. Sensitivity analyses did not change the conclusions. CONCLUSIONS: Probiotics for VAP prevention among critically ill patients were not cost-effective. Study registration data www. CLINICALTRIALS: gov (NCT01782755); registered 4 February 2013.

RéSUMé: OBJECTIF: Nous avons cherché à comparer le rapport coût-efficacité d'un traitement avec probiotiques ajoutés aux soins habituels avec des soins habituels prodigués sans probiotiques chez les patients des soins intensifs sous ventilation mécanique dans le cadre de l'étude PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial). MéTHODE: Nous avons réalisé une évaluation de l'économie de la santé parallèlement à l'étude randomisée contrôlée PROSPECT (octobre 2013-mars 2019). Nous avons adopté le point de vue d'un payeur public de services de santé. Quarante-quatre unités de soins intensifs dans trois pays (Canada/États-Unis/Arabie saoudite) prenant soin de patients adultes gravement malades sous ventilation mécanique (n = 2650) ont été inclus. Les interventions ont été les suivantes : probiotiques (Lactobacillus rhamnosus GG) vs placebo administrés par voie entérale deux fois par jour. Nous avons recueilli les données concernant l'utilisation des ressources en soins de santé et estimé les coûts unitaires en dollars américains (USD) de 2019 sur un horizon temporel allant de la randomisation au congé de l'hôpital / décès. Nous avons calculé des rapports coût-efficacité différentiels (RCED) en comparant les probiotiques vs les soins habituels. Le critère d'évaluation principal était le coût différentiel par événement évité de pneumonie associée au ventilateur (PAV); les critères d'évaluation secondaires étaient les coûts par diarrhée associée au Clostridioides difficile (DACD), diarrhée associée aux antibiotiques (DAA) et mortalité évitées. L'incertitude a été étudiée à l'aide d'analyses d'amorçage et de sensibilité non paramétriques. RéSULTATS: Le coût moyen (écart type [ÉT]) par patient était de 66 914 (91 098) USD pour les patients randomisés au groupe probiotiques, avec une médiane [écart interquartile (ÉIQ)] de 42 947 USD [22 239 à 76 205]. En comparaison, pour ceux ne recevant pas de probiotiques, le coût moyen (ÉT) par patient était de 62 701 USD (78 676) (médiane [ÉIQ], 41 102 USD [23 170 à 75 140]; coût différentiel, 4213 USD; intervalle de confiance [IC] à 95%, -2269 à 10 708). En matière de rapports coût-efficacité différentiels pour les événements de PAV ou DAA évités, les probiotiques étaient dominés par les soins habituels (plus coûteux, avec une efficacité similaire). Les RCED étaient de 1 473 400 USD par événement de DACD évitée (IC 95 %, non défini) et de 396 764 USD par décès évité (IC 95 %, non défini). Les courbes d'acceptabilité coût-efficacité révèlent que les probiotiques n'étaient pas rentables dans de larges gammes de seuils plausibles de volonté de payer. Les analyses de sensibilité n'ont pas modifié les conclusions. CONCLUSION: Les probiotiques utilisés pour prévenir la PAV chez les patients gravement malades n'étaient pas rentables. Enregistrement de l'étude : www.clinicaltrials.gov (NCT01782755); enregistrée le 4 février 2013.