Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults.

BACKGROUND: Whether the use of balanced multielectrolyte solution (BMES) in preference to 0.9% sodium chloride solution (saline) in critically ill patients reduces the risk of acute kidney injury or death is uncertain. METHODS: In a double-blind, randomized, controlled trial, we assigned critically ill patients to receive BMES (Plasma-Lyte 148) or saline as fluid therapy in the intensive care unit (ICU) for 90 days. The primary outcome was death from any cause within 90 days after randomization. Secondary outcomes were receipt of new renal-replacement therapy and the maximum increase in the creatinine level during ICU stay. RESULTS: A total of 5037 patients were recruited from 53 ICUs in Australia and New Zealand - 2515 patients were assigned to the BMES group and 2522 to the saline group. Death within 90 days after randomization occurred in 530 of 2433 patients (21.8%) in the BMES group and in 530 of 2413 patients (22.0%) in the saline group, for a difference of -0.15 percentage points (95% confidence interval [CI], -3.60 to 3.30; P = 0.90). New renal-replacement therapy was initiated in 306 of 2403 patients (12.7%) in the BMES group and in 310 of 2394 patients (12.9%) in the saline group, for a difference of -0.20 percentage points (95% CI, -2.96 to 2.56). The mean (±SD) maximum increase in serum creatinine level was 0.41±1.06 mg per deciliter (36.6±94.0 µmol per liter) in the BMES group and 0.41±1.02 mg per deciliter (36.1±90.0 µmol per liter) in the saline group, for a difference of 0.01 mg per deciliter (95% CI, -0.05 to 0.06) (0.5 µmol per liter [95% CI, -4.7 to 5.7]). The number of adverse and serious adverse events did not differ meaningfully between the groups. CONCLUSIONS: We found no evidence that the risk of death or acute kidney injury among critically ill adults in the ICU was lower with the use of BMES than with saline. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; PLUS ClinicalTrials.gov number, NCT02721654.).

From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

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.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Conservative Oxygen Therapy during Mechanical Ventilation in the ICU.

BACKGROUND: Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio2) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation). METHODS: We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservative-oxygen group, the upper limit of the Spo2 alarm was set to sound when the level reached 97%, and the Fio2 was decreased to 0.21 if the Spo2 was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio2 or the Spo2. The primary outcome was the number of ventilator-free days from randomization until day 28. RESULTS: The number of ventilator-free days did not differ significantly between the conservative-oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [CI], -2.1 to 1.6; P = 0.80). The conservative-oxygen group spent more time in the ICU with an Fio2 of 0.21 than the usual-oxygen group, with a median duration of 29 hours (interquartile range, 5 to 78) and 1 hour (interquartile range, 0 to 17), respectively (absolute difference, 28 hours; 95% CI, 22 to 34); the conservative-oxygen group spent less time with an Spo2 exceeding 96%, with a duration of 27 hours (interquartile range, 11 to 63.5) and 49 hours (interquartile range, 22 to 112), respectively (absolute difference, 22 hours; 95% CI, 14 to 30). At 180 days, mortality was 35.7% in the conservative-oxygen group and 34.5% in the usual-oxygen group, for an unadjusted odds ratio of 1.05 (95% CI, 0.81 to 1.37). CONCLUSIONS: In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the Health Research Council of New Zealand; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.).

Lymphopenia in sepsis-an acquired immunodeficiency?

Sepsis is a global health priority, yet effective host-directed targeted therapies have not been identified outside of the setting of coronavirus disease 2019 (COVID-19). Lymphopenia occurs in up to ~52% of patients with sepsis and is associated with a higher mortality at both 30 and 100 days. In COVID-19, the presence of lymphopenia correlates with intensive care unit admission, acute respiratory distress syndrome and death. The mechanisms underpinning lymphopenic sepsis remain unknown, and while high rates of lymphocyte apoptosis have been implicated, the relative contributions of cellular trafficking to inflamed tissues and reduction in lymphopoiesis require investigation. Further delineation of these underlying mechanisms holds the potential to open new avenues for the development of host-directed therapies in lymphopenic sepsis. These may include recombinant cytokines (e.g. interleukin-7), monoclonal antibodies (e.g. anti-interleukin-1, anti-programmed cell death protein 1) and small interfering RNA (e.g. targeting interleukin-10, transforming growth factor beta). Applying the frontier tools of translational cellular and genomic medicine to understand lymphopenia in the setting of critical infections holds the potential to significantly reduce the excessive global burden of sepsis.

Mortality As a Measure of Treatment Effect in Clinical Trials Recruiting Critically Ill Patients.

OBJECTIVES: All-cause mortality is a common measure of treatment effect in ICU-based randomized clinical trials (RCTs). We sought to understand the performance characteristics of a mortality endpoint by evaluating its temporal course, responsiveness to differential treatment effects, and impact when used as an outcome measure in trials of acute illness. DATA SOURCES: We searched OVID Medline for RCTs published from 1990 to 2018. STUDY SELECTION: We reviewed RCTs that had randomized greater than or equal to 100 patients, were published in one of five high-impact general medical or eight critical care journals, and reported mortality at two or more distinct time points. We excluded trials recruiting pediatric or neonatal patients and cluster RCTs. DATA EXTRACTION: Mortality by randomization group was recorded from the article or estimated from survival curves. Trial impact was assessed by inclusion of results in clinical practice guidelines. DATA SYNTHESIS: From 2,592 potentially eligible trials, we included 343 RCTs (228,784 adult patients). While one third of all deaths by 180 days had occurred by day 7, the risk difference between study arms continued to increase until day 60 (p = 0.01) and possibly day 90 (p = 0.07) and remained stable thereafter. The number of deaths at ICU discharge approximated those at 28-30 days (95% [interquartile range [IQR], 86-106%]), and deaths at hospital discharge approximated those at 60 days (99% [IQR, 94-104%]). Only 13 of 43 interventions (30.2%) showing a mortality benefit have been adopted into widespread clinical practice. CONCLUSIONS: Our findings provide a conceptual framework for choosing a time horizon and interpreting mortality outcome in trials of acute illness. Differential mortality effects persist for 60 to 90 days following recruitment. Location-based measures approximate time-based measures for trials conducted outside the United States. The documentation of a mortality reduction has had a modest impact on practice.

Association of early mobility with the incidence of deep-vein thrombosis and mortality among critically ill patients: a post hoc analysis of PREVENT trial.

BACKGROUND: This study assessed the mobility levels among critically ill patients and the association of early mobility with incident proximal lower-limb deep-vein thrombosis and 90-day mortality. METHODS: This was a post hoc analysis of the multicenter PREVENT trial, which evaluated adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis with an expected ICU stay ≥ 72 h and found no effect on the primary outcome of incident proximal lower-limb deep-vein thrombosis. Mobility levels were documented daily up to day 28 in the ICU using a tool with an 8-point ordinal scale. We categorized patients according to mobility levels within the first 3 ICU days into three groups: early mobility level 4-7 (at least active standing), 1-3 (passive transfer from bed to chair or active sitting), and 0 (passive range of motion). We evaluated the association of early mobility and incident lower-limb deep-vein thrombosis and 90-day mortality by Cox proportional models adjusting for randomization and other co-variables. RESULTS: Of 1708 patients, only 85 (5.0%) had early mobility level 4-7 and 356 (20.8%) level 1-3, while 1267 (74.2%) had early mobility level 0. Patients with early mobility levels 4-7 and 1-3 had less illness severity, femoral central venous catheters, and organ support compared to patients with mobility level 0. Incident proximal lower-limb deep-vein thrombosis occurred in 1/85 (1.3%) patients in the early mobility 4-7 group, 7/348 (2.0%) patients in mobility 1-3 group, and 50/1230 (4.1%) patients in mobility 0 group. Compared with early mobility group 0, mobility groups 4-7 and 1-3 were not associated with differences in incident proximal lower-limb deep-vein thrombosis (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI] 0.16, 8.90; p = 0.87 and 0.91, 95% CI 0.39, 2.12; p = 0.83, respectively). However, early mobility groups 4-7 and 1-3 had lower 90-day mortality (aHR 0.47, 95% CI 0.22, 1.01; p = 0.052, and 0.43, 95% CI 0.30, 0.62; p < 0.0001, respectively). CONCLUSIONS: Only a small proportion of critically ill patients with an expected ICU stay ≥ 72 h were mobilized early. Early mobility was associated with reduced mortality, but not with different incidence of deep-vein thrombosis. This association does not establish causality, and randomized controlled trials are required to assess whether and to what extent this association is modifiable. TRIAL REGISTRATION: The PREVENT trial is registered at ClinicalTrials.gov, ID: NCT02040103 (registered on 3 November 2013) and Current controlled trials, ID: ISRCTN44653506 (registered on 30 October 2013).

The Effect of a Liberal Approach to Glucose Control in Critically Ill Patients with Type 2 Diabetes: A Multicenter, Parallel-Group, Open-Label Randomized Clinical Trial.

Rationale: Blood glucose concentrations affect outcomes in critically ill patients, but the optimal target blood glucose range in those with type 2 diabetes is unknown. Objectives: To evaluate the effects of a "liberal" approach to targeted blood glucose range during ICU admission. Methods: This mutlicenter, parallel-group, open-label randomized clinical trial included 419 adult patients with type 2 diabetes expected to be in the ICU on at least three consecutive days. In the intervention group intravenous insulin was commenced at a blood glucose >252 mg/dl and titrated to a target range of 180-252 mg/dl. In the comparator group insulin was commenced at a blood glucose >180 mg/dl and titrated to a target range of 108-180 mg/dl. The primary outcome was incident hypoglycemia (<72 mg/dl). Secondary outcomes included glucose metrics and clinical outcomes. Measurements and Main Results: By Day 28, at least one episode of hypoglycemia occurred in 10 of 210 (5%) patients assigned the intervention and 38 of 209 (18%) patients assigned the comparator (incident rate ratio, 0.21 [95% confidence interval (CI), 0.09 to 0.49]; P < 0.001). Those assigned the intervention had greater blood glucose concentrations (daily mean, minimum, maximum), less glucose variability, and less relative hypoglycemia (P < 0.001 for all comparisons). By Day 90, 62 of 210 (29.5%) in the intervention and 52 of 209 (24.9%) in the comparator group had died (absolute difference, 4.6 percentage points [95% CI, -3.9% to 13.2%]; P = 0.29). Conclusions: A liberal approach to blood glucose targets reduced incident hypoglycemia but did not improve patient-centered outcomes. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12616001135404).

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.

Sepsis-coded hospitalisations and associated costs in Australia: a retrospective analysis.

OBJECTIVE: To report trends in Australian hospitalisations coded for sepsis and their associated costs. DESIGN: Retrospective analysis of Australian national hospitalisation data from 2002 to 2021. METHODS: Sepsis-coded hospitalisations were identified using the Global Burden of Disease study sepsis-specific ICD-10 codes modified for Australia. Costs were calculated using Australian-Refined Diagnosis Related Group codes and National Hospital Cost Data Collection. RESULTS: Sepsis-coded hospitalisations increased from 36,628 in 2002-03 to 131,826 in 2020-21, an annual rate of 7.8%. Principal admission diagnosis codes contributed 13,843 (37.8%) in 2002-03 and 44,186 (33.5%) in 2020-21; secondary diagnosis codes contributed 22,785 (62.2%) in 2002-03 and 87,640 (66.5%) in 2020-21. Unspecified sepsis was the most common sepsis code, increasing from 15,178 hospitalisations in 2002-03 to 68,910 in 2020-21. The population-based incidence of sepsis-coded hospitalisations increased from 18.6 to 10,000 population (2002-03) to 51.3 per 10,000 (2021-21); representing an increase from 55.1 to 10,000 hospitalisations in 2002-03 to 111.4 in 2020-21. Sepsis-coded hospitalisations occurred more commonly in the elderly; those aged 65 years or above accounting for 20,573 (55.6%) sepsis-coded hospitalisations in 2002-03 and 86,135 (65.3%) in 2020-21. The cost of sepsis-coded hospitalisations increased at an annual rate of 20.6%, from AUD199M (€127 M) in financial year 2012 to AUD711M (€455 M) in 2019. CONCLUSION: Hospitalisations coded for sepsis and associated costs increased significantly from 2002 to 2021 and from 2012 to 2019, respectively.

Sepsis triggers and tools to support early identification in healthcare settings: An integrative review.

BACKGROUND: There is no universal trigger or tool to aid sepsis diagnosis. OBJECTIVES: The objective of this study was to identify triggers and tools to assist the early detection of sepsis that can be readily implemented across various health care settings. METHODS: A systematic integrative review was conducted using MEDLINE, CINAHL, EMBASE, Scopus, and the Cochrane Database of Systematic Reviews. Relevant grey literature and subject-matter expert consultation also informed the review. Study types included systematic reviews, randomised controlled trials, and cohort studies. All patient populations across prehospital, emergency department, and acute hospital inpatient settings, excluding the intensive care unit, were included. Sepsis triggers and tools were evaluated for efficacy in detecting sepsis and association with process measures and patient outcomes. Methodological quality was appraised using Joanna Briggs Institute tools. RESULTS: Of the 124 included studies, most were retrospective cohort (49.2%) in adults (83.9%) within the emergency department (44.4%). The most commonly evaluated sepsis tools were qSOFA (12 studies) and SIRS (11 studies) with a median sensitivity of 28.0% versus 51.0% and a specificity of 98.0% versus 82.0%, respectively, for sepsis diagnosis. Lactate plus qSOFA (two studies) had a sensitivity between 57.0 and 65.5%, whereas the National Early Warning Score (four studies) demonstrated median sensitivity and specificity >80%, but the latter was considered difficult to implement. Amongst triggers, lactate (18 studies) at the threshold of ≥2.0 mmol/L showed higher sensitivity for predicting sepsis-related clinical deterioration than <2.0 mmol/L. Automated sepsis alerts and algorithms (35 studies) showed median sensitivity between 58.0 and 80.0% and specificity between 60.0 and 93.1%. There were limited data for other sepsis tools and maternal, paediatric, and neonatal populations. Overall methodological quality was high. CONCLUSION: No single sepsis tool or trigger is applicable across various settings and populations, but considering efficacy and ease of implementation, there is evidence to use lactate plus qSOFA for adult patients. More research is needed in maternal, paediatric, and neonatal populations.

Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

BACKGROUND: Whether adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis would result in a lower incidence of deep-vein thrombosis than pharmacologic thromboprophylaxis alone is uncertain. METHODS: We randomly assigned patients who were considered adults according to the local standards at the participating sites (≥14, ≥16, or ≥18 years of age) within 48 hours after admission to an intensive care unit (ICU) to receive either intermittent pneumatic compression for at least 18 hours each day in addition to pharmacologic thromboprophylaxis with unfractionated or low-molecular-weight heparin (pneumatic compression group) or pharmacologic thromboprophylaxis alone (control group). The primary outcome was incident (i.e., new) proximal lower-limb deep-vein thrombosis, as detected on twice-weekly lower-limb ultrasonography after the third calendar day since randomization until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first. RESULTS: A total of 2003 patients underwent randomization - 991 were assigned to the pneumatic compression group and 1012 to the control group. Intermittent pneumatic compression was applied for a median of 22 hours (interquartile range, 21 to 23) daily for a median of 7 days (interquartile range, 4 to 13). The primary outcome occurred in 37 of 957 patients (3.9%) in the pneumatic compression group and in 41 of 985 patients (4.2%) in the control group (relative risk, 0.93; 95% confidence interval [CI], 0.60 to 1.44; P = 0.74). Venous thromboembolism (pulmonary embolism or any lower-limb deep-vein thrombosis) occurred in 103 of 991 patients (10.4%) in the pneumatic compression group and in 95 of 1012 patients (9.4%) in the control group (relative risk, 1.11; 95% CI, 0.85 to 1.44), and death from any cause at 90 days occurred in 258 of 990 patients (26.1%) and 270 of 1011 patients (26.7%), respectively (relative risk, 0.98; 95% CI, 0.84 to 1.13). CONCLUSIONS: Among critically ill patients who were receiving pharmacologic thromboprophylaxis, adjunctive intermittent pneumatic compression did not result in a significantly lower incidence of proximal lower-limb deep-vein thrombosis than pharmacologic thromboprophylaxis alone. (Funded by King Abdulaziz City for Science and Technology and King Abdullah International Medical Research Center; PREVENT ClinicalTrials.gov number, NCT02040103; Current Controlled Trials number, ISRCTN44653506.).

Determinants of Adherence to Best Practice in Severe Traumatic Brain Injury: A Qualitative Study.

BACKGROUND: Management of patients with severe traumatic brain injury (sTBI) is highly variable and inconsistently aligned with evidence derived from high-quality trials, including those examining intravenous fluid resuscitation and use of decompressive craniectomy surgery. This study explored the barriers and facilitators of general and specific evidence-based practices in sTBI from the perspectives of stakeholder clinicians. METHODS: This was a qualitative study of semistructured interviews conducted with specialist clinicians responsible for acute care of patients with sTBI. Interview analysis was guided by the Theoretical domains framework (TDF), and key themes were mapped to relevant TDF behavioral domains. RESULTS: Ten neurosurgeons, 12 intensive care specialists, and three trauma physicians from six high-income countries participated between May 2020 and May 2021. Key TDF domains were environmental context and resources, social influences, and beliefs about consequences. Evidence-aligned management of patients with sTBI is perceived to be facilitated by admission to academic research-oriented hospitals, development of local practice protocols, and interdisciplinary collaboration. Determinants of specific practices varied and included health policy change for fluid resuscitation and development of patient-centered goals for surgical decision-making. CONCLUSIONS: In choosing interventions for patients with sTBI, clinicians integrate local environmental, social, professional, and emotional influences with evidence and associated clinical practice guideline recommendations. This study highlights determinants of evidence-based practice that may inform implementation efforts and thereby improve outcomes for patients with sTBI.

Association Between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis.

Importance: The effectiveness of selective decontamination of the digestive tract (SDD) in critically ill adults receiving mechanical ventilation is uncertain. Objective: To determine whether SDD is associated with reduced risk of death in adults receiving mechanical ventilation in intensive care units (ICUs) compared with standard care. Data Sources: The primary search was conducted using MEDLINE, EMBASE, and CENTRAL databases until September 2022. Study Selection: Randomized clinical trials including adults receiving mechanical ventilation in the ICU comparing SDD vs standard care or placebo. Data Extraction and Synthesis: Data extraction and risk of bias assessments were performed in duplicate. The primary analysis was conducted using a bayesian framework. Main Outcomes and Measures: The primary outcome was hospital mortality. Subgroups included SDD with an intravenous agent compared with SDD without an intravenous agent. There were 8 secondary outcomes including the incidence of ventilator-associated pneumonia, ICU-acquired bacteremia, and the incidence of positive cultures of antimicrobial-resistant organisms. Results: There were 32 randomized clinical trials including 24 389 participants in the analysis. The median age of participants in the included studies was 54 years (IQR, 44-60), and the median proportion of female trial participants was 33% (IQR, 25%-38%). Data from 30 trials including 24 034 participants contributed to the primary outcome. The pooled estimated risk ratio (RR) for mortality for SDD compared with standard care was 0.91 (95% credible interval [CrI], 0.82-0.99; I2 = 33.9%; moderate certainty) with a 99.3% posterior probability that SDD reduced hospital mortality. The beneficial association of SDD was evident in trials with an intravenous agent (RR, 0.84 [95% CrI, 0.74-0.94]), but not in trials without an intravenous agent (RR, 1.01 [95% CrI, 0.91-1.11]) (P value for the interaction between subgroups = .02). SDD was associated with reduced risk of ventilator-associated pneumonia (RR, 0.44 [95% CrI, 0.36-0.54]) and ICU-acquired bacteremia (RR, 0.68 [95% CrI, 0.57-0.81]). Available data regarding the incidence of positive cultures of antimicrobial-resistant organisms were not amenable to pooling and were of very low certainty. Conclusions and Relevance: Among adults in the ICU treated with mechanical ventilation, the use of SDD compared with standard care or placebo was associated with lower hospital mortality. Evidence regarding the effect of SDD on antimicrobial resistance was of very low certainty.

Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain. Objective: To determine whether SDD reduces in-hospital mortality in critically ill adults. Design, Setting, and Participants: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021. Interventions: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care. Main Outcomes and Measures: The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs. Results: Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively. Conclusions and Relevance: Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT02389036.

Long-term costs and cost-effectiveness of adjunctive corticosteroids for patients with septic shock in New Zealand.

OBJECTIVE: The aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. DESIGN: This is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. SETTING: The study was conducted in New Zealand. PARTICIPANTS AND INTERVENTION: Patients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. MAIN OUTCOME MEASURES: Healthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. RESULTS: Of 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. CONCLUSIONS: In New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.

Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.

BACKGROUND: Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. METHODS: We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. FINDINGS: In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. INTERPRETATION: Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. FUNDING: The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.