Daily Sepsis Research Analysis
A multicenter randomized trial (TARTARE-2S) found that targeting tissue perfusion while allowing lower MAP in septic shock did not improve days alive without vasopressors and with normalized lactate, but appeared safe. Mechanistically, histone H3K18 lactylation via p300 upregulated PAD4, driving NETosis and worsening septic acute kidney injury in preclinical models, highlighting PAD4/lactylation as therapeutic targets. An engineering study introduced a rapid MOF-based microfluidic chip enabling
Summary
A multicenter randomized trial (TARTARE-2S) found that targeting tissue perfusion while allowing lower MAP in septic shock did not improve days alive without vasopressors and with normalized lactate, but appeared safe. Mechanistically, histone H3K18 lactylation via p300 upregulated PAD4, driving NETosis and worsening septic acute kidney injury in preclinical models, highlighting PAD4/lactylation as therapeutic targets. An engineering study introduced a rapid MOF-based microfluidic chip enabling multianalyte, point-of-care sepsis assessment with improved diagnostic accuracy when combining procalcitonin with ascorbic acid.
Research Themes
- Hemodynamic targets and tissue perfusion in septic shock resuscitation
- Epigenetic regulation (histone lactylation) of NETosis in septic AKI
- Point-of-care, multi-marker diagnostics for sepsis
Selected Articles
1. Targeted Tissue Perfusion Versus Macrocirculatory-Guided Standard Care in Patients With Septic Shock: A Randomized Clinical Trial-The TARTARE-2S Trial.
In 219 adults with septic shock and lactate >3 mmol/L, targeting tissue perfusion with a lower MAP goal (50–65 mm Hg) did not increase 30-day days alive with normal lactate and without vasopressors/inotropes versus MAP-guided standard care. Mortality and organ-support–free days were similar, and no additional safety issues emerged despite lower achieved MAP in the TTP arm.
Impact: This multicenter RCT directly tests a core resuscitation paradigm, informing whether lower MAP targets guided by bedside perfusion indices are safe and effective in septic shock.
Clinical Implications: Clinicians may integrate peripheral perfusion assessments (e.g., capillary refill time) without strictly maintaining higher MAP targets, avoiding overtreatment when tissue perfusion appears adequate. However, routine adoption of lower MAP targets cannot be recommended for improving outcomes based on these data.
Key Findings
- Primary outcome (days alive with normal lactate and without vasoactive drugs at 30 days) was similar between TTP and standard care.
- 30-day mortality was comparable (24.7% TTP vs 27.8% SC).
- Achieved MAP was lower in TTP without excess serious adverse reactions.
- Secondary outcomes (organ support–free days) did not differ significantly.
Methodological Strengths
- Randomized, multicenter design with stratified allocation.
- Prespecified composite primary endpoint integrating lactate normalization and vasopressor-free days.
Limitations
- Open-label design with potential performance bias.
- Modest sample size may limit power for mortality differences; enrolled in European ICUs only.
Future Directions: Evaluate personalized MAP/perfusion targets in larger, blinded-outcome trials, including subgroups (e.g., chronic hypertension) and integration with dynamic perfusion indices and microcirculatory monitoring.
2. Histone Lactylation-Mediated PAD4 Up-Regulation Promotes Septic Acute Kidney Injury via Activating NETosis.
In CLP-induced septic rats and LPS-stimulated renal cells, p300-mediated H3K18 histone lactylation upregulated PAD4, promoting NETosis and worsening renal injury. PAD4 levels correlated with serum lactate, and inhibiting PAD4 or histone lactylation suppressed NETosis and ameliorated SAKI, nominating PAD4/lactylation as therapeutic targets.
Impact: This work uncovers an epigenetic mechanism linking lactate metabolism to PAD4-driven NETosis in septic AKI, offering actionable targets (PAD4, p300/lactylation) for intervention.
Clinical Implications: Although preclinical, findings support exploring PAD4 inhibitors or modulators of histone lactylation (e.g., p300 inhibitors) to mitigate NETosis and renal injury in sepsis, and motivate biomarker development around PAD4/lactate signatures.
Key Findings
- PAD4 and serum lactate were elevated in SAKI and positively correlated.
- p300-mediated H3K18 lactylation increased PAD4 expression in response to LPS.
- Inhibiting PAD4 or histone lactylation suppressed NETosis and alleviated renal injury in septic rats.
- citH3 and NETosis markers decreased with PAD4/lactylation inhibition.
Methodological Strengths
- Integrated in vivo CLP model with in vitro LPS-stimulated cell assays.
- Mechanistic validation using ChIP for p300 binding and functional inhibition of PAD4/lactylation.
Limitations
- Preclinical animal and cell models; lack of human validation.
- Exact sample sizes and dosing regimens are not detailed in the abstract.
Future Directions: Translate to human studies by measuring PAD4/lactylation in septic AKI, test PAD4 or p300 inhibitors in relevant models, and assess NETosis-modulating therapies’ safety and efficacy.
3. Valence-Manipulated Coordination MOF-Based Probes for Multidimensional Point-of-Care Diagnosis.
A microfluidic chip enabling in situ synthesis of reversible MARS-Cu nanoparticles allows rapid (~25 min) dual-marker measurement (procalcitonin and ascorbic acid) for sepsis assessment. Combining both indicators improved diagnostic accuracy from 84.3% (procalcitonin alone) to 100% in this proof-of-concept, supporting multidimensional point-of-care diagnostics.
Impact: Introduces a fast, reversible MOF-based probe platform for multi-marker, point-of-care sepsis diagnostics with substantial accuracy gains when combining markers.
Clinical Implications: If validated clinically, such chips could shorten time-to-decision, enable decentralized testing, and improve triage by integrating multiple pathophysiologic axes beyond a single biomarker.
Key Findings
- Developed a microfluidic chip enabling 40-second in situ synthesis of reversible MARS-Cu nanoparticles.
- Achieved rapid (~25 min) dual-marker detection of procalcitonin and ascorbic acid on-chip.
- Combining procalcitonin with ascorbic acid increased sepsis diagnostic accuracy from 84.3% to 100% in this study.
- Demonstrated one-chip operation and multi-category analysis for clinical diagnostics.
Methodological Strengths
- Integrated chemistry and microfluidics enabling rapid, room-temperature nanoparticle synthesis.
- Demonstrated multi-marker detection with defined analytical turnaround and performance improvement over single-marker testing.
Limitations
- Clinical sample size and external validation details are not specified; risk of overestimation in proof-of-concept.
- Ascorbic acid’s specificity for sepsis states requires broader pathophysiologic validation.
Future Directions: Prospective, multicenter diagnostic accuracy and impact studies comparing against current standards (e.g., PCT, CRP, qSOFA/SOFA) with clinical outcomes, and assessment of robustness in diverse settings.