Daily Sepsis Research Analysis
Three impactful sepsis papers stood out today: a first-in-human phase I trial of a low-anticoagulant heparin (M6229) that neutralizes circulating histones in ICU sepsis; a multicentre study developing an interpretable machine-learning definition of suspected infection for sepsis surveillance with strong external validation; and a comprehensive 2025 S3 guideline update from the German Sepsis Society that aligns with SSC 2021 and exposes persistent evidence gaps.
Summary
Three impactful sepsis papers stood out today: a first-in-human phase I trial of a low-anticoagulant heparin (M6229) that neutralizes circulating histones in ICU sepsis; a multicentre study developing an interpretable machine-learning definition of suspected infection for sepsis surveillance with strong external validation; and a comprehensive 2025 S3 guideline update from the German Sepsis Society that aligns with SSC 2021 and exposes persistent evidence gaps.
Research Themes
- Histone-targeted therapeutics in sepsis
- AI-enabled operational definitions for sepsis surveillance
- Guideline-driven standardization and evidence gaps in sepsis care
Selected Articles
1. Development and validation of an interpretable machine learning model for retrospective identification of suspected infection for sepsis surveillance: a multicentre cohort study.
Using chart review as the reference, an interpretable gradient boosting model accurately identified suspected infection among ED patients with qSOFA ≥2 (F1 85.9%; external F1 85.7%), outperforming Sepsis-3, ASE, and ICD-based proxies in sensitivity. Most predictive features captured inflammatory response or clinician actions, while performance was lower for hospital-onset cases.
Impact: This work operationalizes 'suspected infection' with transparent ML and strong external validation, addressing a core bottleneck in sepsis surveillance metrics and enabling more accurate epidemiologic tracking and quality measurement.
Clinical Implications: Health systems could adopt ML-augmented surveillance definitions that include inflammatory response to improve case ascertainment and benchmarking; bedside decision-making should await prospective validation and broader setting evaluation.
Key Findings
- Gradient boosting achieved F1 85.9%, sensitivity 91.1%, specificity 89.0% in ED derivation; external validation F1 85.7%, sensitivity 87.5%, specificity 92.5%.
- Outperformed Sepsis-3 (sensitivity 78.9%), adapted ASE (85.6%), and ICD codes (33.3%) for community-onset cases.
- Model features predominantly reflected inflammatory response (e.g., CRP, temperature) and infection-related actions (antibiotics, cultures).
- Hospital-onset sepsis detection was weaker (best F1 52.2% with logistic regression).
Methodological Strengths
- Multicentre design with external validation across time and site.
- Manual chart review used as the reference standard for sepsis identification.
- Interpretable features aligned with clinical reasoning (inflammation and actions).
Limitations
- Restricted to patients with qSOFA ≥2, limiting generalizability to milder cases.
- Retrospective EHR-based study in the Netherlands; international validation needed.
- Performance for hospital-onset sepsis was modest.
Future Directions: Prospective implementation trials, adaptation to other organ dysfunction criteria beyond qSOFA, and multinational validation to establish robust surveillance benchmarks.
2. A phase I trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered low-anticoagulant heparin (M6229) in critically ill sepsis patients.
First-in-human dose-escalation of M6229 in ICU sepsis demonstrated acceptable safety up to 0.9 mg/kg/h over 6 hours, with proportional aPTT changes and rapid reversal after infusion. Pharmacodynamic signals indicated intravascular histone engagement (H3/H2b changes and H3 cleavage) and SOFA score decreased in 70% of patients.
Impact: Targets a fundamental DAMP mechanism in sepsis (extracellular histones) with a low-anticoagulant heparin, providing mechanistic biomarker evidence and a tolerable dosing window in actual ICU patients.
Clinical Implications: Supports advancing M6229 into efficacy trials to test whether histone neutralization reduces organ failure and mortality without bleeding risk; offers a potential adjunct to standard sepsis care.
Key Findings
- Maximum tolerated dose established at 0.9 mg/kg/h over 6 hours using mCRM; one DLPE (aPTT 100 s).
- Dose-proportional pharmacokinetics and rapid normalization of aPTT post-infusion; no serious infusion-related adverse events.
- PD evidence of histone engagement: increased plasma H3/H2b and proteolytic cleavage of H3 in 4/5 evaluable patients.
- SOFA scores decreased in the days after infusion in 70% of patients.
Methodological Strengths
- Model-based dose escalation (mCRM) with overdose control in critically ill patients.
- Integrated PK/PD and mechanistic biomarkers indicating target engagement.
Limitations
- Small, single-centre, nonrandomized phase I design without a control arm.
- Clinical improvements (e.g., SOFA decrease) are exploratory and confounded.
Future Directions: Proceed to randomized, multicentre phase II trials to evaluate efficacy on organ failure and survival, refine dosing, and monitor bleeding and arrhythmia (QTc) risks.
3. [S3 guideline on sepsis-prevention, diagnosis, therapy, and follow-up care-update 2025].
The 2025 S3 guideline update addresses 88 PICO questions, issuing 57 evidence-based recommendations (26 strong, 31 weak) with alignment to SSC 2021. The guideline highlights that only 5 recommendations are based on high-quality evidence, exposing large gaps and calling for multicentre noncommercial trials, and it emphasizes incorporation into QA 2025 and survivor quality-of-life care.
Impact: Provides a current, GRADE-based national guideline that will shape sepsis care and QA metrics, while transparently mapping evidence deficits to guide research priorities.
Clinical Implications: Updates to diagnostics, infection management, and organ support need integration into institutional protocols and QA indicators; outpatient follow-up should address health-related quality of life in survivors.
Key Findings
- Addressed 88 PICO questions with 57 evidence-based recommendations (26 strong; 31 weak), 29 new and 16 modified compared with 2018.
- Only 5 recommendations had high GRADE evidence; 18 moderate, 17 low, 16 very low, underscoring major evidence gaps.
- Emphasizes incorporation into 2025 QA indicators and prioritizes survivor health-related quality of life in outpatient care.
Methodological Strengths
- Systematic update searches to December 2024 with GRADE methodology and AWMF standards.
- Alignment and cross-walk with SSC 2021 to ensure consistency and transparency.
Limitations
- Guideline recommendations are constrained by low to very low evidence in many areas.
- National context may limit generalizability outside Germany.
Future Directions: Calls for multicentre, noncommercial clinical trials to fill prioritized evidence gaps and ongoing guideline updates as new data emerge.