Daily Sepsis Research Analysis
Three studies reshape sepsis care: a multicenter target trial emulation suggests corticosteroid effects depend on predicted organ dysfunction trajectories; a meta-analysis of RCTs indicates critical care ultrasonography may reduce mortality and fluid balance; and an RCT-only meta-analysis finds sepsis early warning systems do not improve mortality or key process outcomes, challenging current screening recommendations.
Summary
Three studies reshape sepsis care: a multicenter target trial emulation suggests corticosteroid effects depend on predicted organ dysfunction trajectories; a meta-analysis of RCTs indicates critical care ultrasonography may reduce mortality and fluid balance; and an RCT-only meta-analysis finds sepsis early warning systems do not improve mortality or key process outcomes, challenging current screening recommendations.
Research Themes
- Precision stratification of immunomodulatory therapy in sepsis
- Ultrasound-guided fluid management in critical care
- Reappraisal of sepsis screening effectiveness
Selected Articles
1. Multicenter target trial emulation to evaluate corticosteroids for sepsis stratified by predicted organ dysfunction trajectory.
Using a two-stage machine learning pipeline to subphenotype and predict organ dysfunction trajectories, the authors emulated a target trial across multiple cohorts of sepsis, pneumonia, and ARDS. The association between corticosteroid use and 28-day mortality differed by predicted trajectory and across cohorts, suggesting treatment effect heterogeneity aligned with pathobiology.
Impact: Introduces a pragmatic precision-medicine framework to tailor steroids by predicted organ dysfunction trajectories, potentially reconciling mixed trial results.
Clinical Implications: Clinicians should consider that corticosteroid benefit may depend on dynamic organ dysfunction trajectories; future protocols could incorporate early trajectory prediction to guide steroid use.
Key Findings
- Two-stage ML (subphenotyping then prediction) classified patients by organ dysfunction trajectory.
- Target trial emulation showed that corticosteroid–28-day mortality associations varied by predicted trajectory.
- Heterogeneous effects were observed across cohorts of sepsis, pneumonia, and ARDS.
Methodological Strengths
- Multicenter retrospective design with target trial emulation
- Advanced ML subphenotyping and prospective-style stratification
Limitations
- Observational emulation subject to residual confounding and misclassification
- Generalizability and implementation require prospective validation
Future Directions: Prospective, randomized trials stratified by predicted trajectories to test steroid efficacy; integration of trajectory prediction tools into clinical decision support.
Corticosteroids decrease the duration of organ dysfunction in sepsis and a range of overlapping and complementary infectious critical illnesses, including septic shock, pneumonia and the acute respiratory distress syndrome (ARDS). The risk and benefit of corticosteroids are not fully defined using the construct of organ dysfunction duration. This retrospective multicenter, proof-of-concept study aimed to evaluate the association between usage of corticosteroids and mortality of patients with sepsis, pneumonia and ARDS by emulating a target trial framework stratified by predicted organ dysfunction trajectory. The study employed a two staged machine learning (ML) methodology to first subphenotype based on organ dysfunction trajectory then predict this defined trajectory. Once patients were classified by predicted trajectory we conducted a target trial emulation. Our analysis revealed that the association between corticosteroid use and 28-day mortality varied by predicted trajectory and between cohorts.Our findings suggest that matching treatment strategies to empirically observed pathobiology may offer a more nuanced understanding of corticosteroid utility.
2. The Effect of Early Warning Systems for Sepsis on Mortality: A Systematic Review and Meta-analysis.
Across 7 randomized trials (n=3409), sepsis early warning systems did not significantly reduce mortality, time to antibiotics, or length of stay; overall evidence certainty was low. The authors call for reconsideration of guideline recommendations that endorse universal sepsis screening.
Impact: Provides RCT-only evidence that challenges widely adopted screening policies, with potential to redirect quality-improvement resources.
Clinical Implications: Hospitals should critically appraise sepsis screening alerts and prioritize interventions with proven benefit; future trials should standardize alert logic and link to actionable protocols.
Key Findings
- Pooled mortality OR with early warning systems: 0.84 (95% CI 0.60–1.18), not significant.
- Time to antibiotics 0.08 hours faster (95% CI −0.44 to 0.28), not significant.
- Length of stay −0.27 days (95% CI −1.21 to 0.66), not significant; overall evidence graded low.
Methodological Strengths
- Restricted to randomized controlled trials with comprehensive database search
- Risk of bias and certainty assessed using Cochrane tool and GRADE; PROSPERO-registered
Limitations
- Low certainty due to bias and imprecision; heterogeneity of alert systems and workflows
- Limited reporting of downstream actions following alerts
Future Directions: Design pragmatic RCTs with standardized alert logic, integration with protocolized care, and patient-centered outcomes; evaluate targeted vs universal screening.
BACKGROUND: The Surviving Sepsis Campaign strongly recommends that all hospitals screen for sepsis as part of performance improvement. The effect of screening for sepsis on mortality, time to antibiotics, and length of stay is uncertain. METHODS: A systematic literature search was conducted using Cochrane Library, Google Scholar, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection from earliest entry to June 1, 2024. We included all randomized controlled studies of any type of alert system to screen adult patients for sepsis. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Outcomes were pooled using random effects meta-analysis. Strength of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: In total, we found 7 studies of 3409 patients with sepsis. The pooled odds ratio for mortality for patients randomized to early warning systems was 0.84 (95% CI, 0.60, 1.18). The average time to antibiotics was reported in 4 studies and found to be 0.08 h faster in the screening group (95% CI, - 0.44, 0.28). Length of stay was reported in 4 studies and found to be 0.27 days less in the screening group (95%, - 1.21, 0.66). All differences were non-significant. Overall strength of evidence was low due to risk of bias and imprecision. CONCLUSIONS: Based on the current body of randomized controlled studies, there is insufficient evidence to recommend screening for sepsis. Guidelines should reconsider current recommendations for screening for sepsis. PROSPERO REGISTRATION: CRD42024563222.
3. Critical Care Ultrasonography for Volume Management: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis of Randomized Trials.
Across 17 RCTs (n=1765), CCUS-guided fluid management may reduce mortality (RR 0.79) and lower cumulative fluid balance within 72 hours, with uncertain effects on ventilation duration, ICU LOS, vasopressor use, AKI, and RRT due to low/very low certainty.
Impact: Synthesizes randomized evidence supporting ultrasound-guided hemodynamic management, quantifying mortality benefit and early fluid stewardship.
Clinical Implications: Incorporate CCUS into fluid decision-making algorithms, emphasizing training and protocolization while acknowledging low certainty and heterogeneity.
Key Findings
- 17 RCTs, 1765 patients: mortality RR 0.79 (95% CI 0.67–0.95).
- Reduced cumulative fluid balance up to 72 hours (MD −0.72 L; 95% CI −1.5 to +0.07 L).
- Uncertain effects on MV duration, ICU LOS, vasopressor use, AKI, and RRT (very low certainty).
Methodological Strengths
- RCT限定の統合、重複独立抽出、ランダム効果モデル
- Cochrane改変ツールとGRADEによるバイアス・確実性評価
Limitations
- Low certainty due to imprecision and indirectness; heterogeneous CCUS protocols and clinician expertise
- Outcome definitions and follow-up timing varied across trials
Future Directions: Large, pragmatic RCTs with standardized CCUS protocols and training, evaluating patient-centered outcomes and cost-effectiveness.
OBJECTIVES: To determine the safety and efficacy of critical care ultrasonography (CCUS) guided volume management in acutely ill patients. DATA SOURCES: We searched MEDLINE, Embase, Wiley CENTRAL, and unpublished sources from inception to February 6, 2024. STUDY SELECTION: We included randomized controlled trials (RCTs) of acutely ill adult patients randomized to receive CCUS as compared with no CCUS to guide fluid management. DATA EXTRACTION: Reviewers screened abstracts, full texts, and extracted data independently and in duplicate. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool and assessed the certainty of evidence using the Grading Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: We included 17 RCTs (n = 1765 patients) in this review. Pooled analyses found that the use of CCUS for volume management in acutely ill patients may decrease mortality at the longest reported time period (relative risk [RR], 0.79; 95% CI, 0.67-0.95; low certainty) and decreases the fluid balance up to 72 hours after admission (mean difference [MD], 0.72 L lower; 95% CI, 1.5 L lower to 0.07 L higher; low certainty). CCUS had an uncertain effect on duration of mechanical ventilation (MD, 1.14 d fewer; 95% CI, 3.35 d fewer to 1.07 d more; very low certainty), ICU length of stay (LOS) (MD, 0.01 d fewer; 95% CI, 1.12 d fewer to 1.09 d more; very low certainty), the need for vasopressors (RR, 0.39; 95% CI, 0.10-1.62; very low certainty), acute kidney injury (AKI) (RR, 0.94; 95% CI, 0.32-2.72; very low certainty), and the need for renal replacement therapy (RRT) (RR, 0.79; 95% CI, 0.17-3.66; very low certainty). CONCLUSIONS: In acutely ill adult patients, CCUS for the use of targeted volume management may reduce mortality and fluid balance up to 72 hours after admission. CCUS has an uncertain effect on ICU LOS, duration of mechanical ventilation, duration of vasopressor use, AKI, and the need for RRT. However, this evidence is limited by imprecision and indirectness.