Daily Sepsis Research Analysis
Today’s top sepsis papers span mechanistic discovery, pragmatic neonatal epidemiology, and a randomized trial of fluid strategy. A Communications Biology study identifies the S100A8/A9–RAGE–Drp1 axis driving mitochondrial fragmentation and muscle atrophy in sepsis. A Lancet Microbe cross-sectional analysis quantifies pathogen patterns and mortality risks in neonatal bloodstream infections in South African lower-tier hospitals, and an RCT shows 20% albumin rapidly improves microcirculation in sep
Summary
Today’s top sepsis papers span mechanistic discovery, pragmatic neonatal epidemiology, and a randomized trial of fluid strategy. A Communications Biology study identifies the S100A8/A9–RAGE–Drp1 axis driving mitochondrial fragmentation and muscle atrophy in sepsis. A Lancet Microbe cross-sectional analysis quantifies pathogen patterns and mortality risks in neonatal bloodstream infections in South African lower-tier hospitals, and an RCT shows 20% albumin rapidly improves microcirculation in septic shock.
Research Themes
- Sepsis pathophysiology and organ dysfunction
- Neonatal sepsis epidemiology and antimicrobial resistance
- Resuscitation fluids and microcirculation-guided therapy
Selected Articles
1. Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
This study links sepsis-induced muscle atrophy to S100A8/A9-driven mitochondrial dysfunction via RAGE-mediated Drp1 phosphorylation and mitochondrial fragmentation. Inhibiting S100A8/A9, ablating RAGE, or blocking Drp1 mitigated mitochondrial damage and muscle atrophy in mice, while clinical data associated ΔSMI with 60-day mortality.
Impact: It uncovers a druggable pathway (S100A8/A9–RAGE–Drp1) underpinning septic myopathy, integrating clinical association with rigorous mechanistic validation. This establishes targets for future therapies aimed at sepsis-related muscle dysfunction.
Clinical Implications: S100A8/A9 and components of the RAGE–Drp1 axis may serve as biomarkers and therapeutic targets to prevent or treat sepsis-associated muscle wasting and weakness, pending human interventional studies.
Key Findings
- ΔSMI was an independent risk factor for 60-day mortality in septic patients.
- Sepsis in mice induced skeletal muscle atrophy linked to upregulated S100a8/a9 and mitochondrial dysfunction.
- Blocking S100a8/a9 improved mitochondrial function and reduced muscle atrophy; recombinant S100a8/a9 worsened both.
- Mechanistically, S100a8/a9 engaged RAGE to phosphorylate Drp1, driving mitochondrial fragmentation; RAGE ablation or Drp1 inhibition rescued mitochondrial morphology and function.
Methodological Strengths
- Integrative design combining clinical retrospective analysis with in vivo CLP models and mechanistic in vitro validation.
- Causal pathway delineation using pharmacologic inhibition, genetic ablation (RAGE), and Drp1 inhibition with mitochondrial functional readouts.
Limitations
- Clinical component is retrospective with unspecified sample size and potential confounding.
- Translational gap remains: no human interventional data targeting the S100A8/A9–RAGE–Drp1 axis.
Future Directions: Prospective human studies to validate S100A8/A9 as a biomarker, and early-phase trials of RAGE or S100A8/A9/Drp1 modulators to prevent ICU-acquired weakness in sepsis.
2. Pathogen aetiology and risk factors for death among neonates with bloodstream infections at lower-tier South African hospitals: a cross-sectional study.
In six lower-tier South African hospitals, neonatal bloodstream infection incidence was 6.4 per 1000 patient-days with 63% Gram-negative pathogens, chiefly Klebsiella pneumoniae and Acinetobacter baumannii. Mortality was 25.5% and independently associated with Gram-negative BSI, inborn late-onset sepsis, preterm birth, and NICU admission.
Impact: Quantifies pathogen burden and risk stratification where resources are limited, directly informing empiric therapy, infection prevention, and health system planning for neonatal sepsis.
Clinical Implications: Strengthen Gram-negative coverage where appropriate, intensify infection prevention in lower-tier hospitals, and prioritize preterm neonates and inborn LOS for targeted interventions.
Key Findings
- Incidence of neonatal bloodstream infection was 6.4 per 1000 patient-days across 907 episodes.
- Gram-negative organisms dominated (63.2%), led by Klebsiella pneumoniae (25.7%) and Acinetobacter baumannii (19.2%).
- Crude in-hospital mortality was 25.5%, accounting for 21.4% of all in-hospital neonatal deaths.
- Independent mortality risk factors included Gram-negative BSI (aOR 3.70), inborn LOS vs EOS (aOR 2.42), preterm birth (aOR 5.00), and NICU admission (aOR 3.26).
Methodological Strengths
- Multi-site dataset from six lower-tier hospitals with standardized categorization of EOS and LOS.
- Adjusted analyses with multivariable logistic regression quantifying independent risk factors.
Limitations
- Cross-sectional observational design limits causal inference and is subject to culture and referral biases.
- Limited detail on antimicrobial exposures, device use, and infection prevention practices that may confound outcomes.
Future Directions: Implement and evaluate infection-prevention bundles and stewardship in lower-tier settings; prospective cohorts to assess time-to-therapy and device-associated risks; genomic surveillance for AMR.
3. Microcirculation properties of 20 % albumin in sepsis; a randomised controlled trial.
In a single-centre RCT of 100 fluid-responsive septic shock patients, 20% albumin boluses improved microvascular density and activity at 15 and 60 minutes compared with crystalloids, despite worse baseline microcirculation. No differences were observed in fluid balance, vasopressor days, ICU length of stay, or mortality.
Impact: Provides randomized evidence that hyperoncotic albumin can rapidly improve microcirculation, supporting microcirculation-guided resuscitation strategies and informing design of outcome-powered trials.
Clinical Implications: For fluid-responsive septic shock, 20% albumin boluses may be considered to acutely improve microcirculation; practice change should await multicentre trials demonstrating patient-centred benefits.
Key Findings
- 20% albumin significantly improved microvascular density and activity at 15 and 60 minutes (p<0.005) versus crystalloids.
- Both groups were fluid responsive (mean pulse pressure variability 17%); baseline microcirculation was worse in the albumin group.
- No significant differences in fluid balance, vasopressor days, ICU length of stay, or mortality between groups.
Methodological Strengths
- Randomised controlled design with trial registration and objective SDF-based microcirculatory assessment.
- Fluid responsiveness confirmed and boluses titrated to clinical effect, enhancing physiologic relevance.
Limitations
- Single-centre study, likely unblinded, and not powered for patient-centred outcomes.
- Baseline microcirculation imbalance; short follow-up for microcirculation endpoints.
Future Directions: Multicentre, outcome-powered RCTs comparing albumin vs crystalloids with microcirculation-guided protocols; subgroup analyses by endothelial glycocalyx injury and albumin levels.