Daily Sepsis Research Analysis
Three studies advanced sepsis care across treatment and prognostication. A multicenter RCT (A2B, JAMA) found dexmedetomidine- or clonidine-based sedation did not shorten ventilation vs propofol and increased bradycardia/agitation. Two Critical Care cohorts linked innate immune biology to outcomes: plasma H3.1 nucleosomes (NETs-derived) predicted organ failure needs, and cirrhotic sepsis showed an endothelial-injury phenotype with higher AKI and mortality.
Summary
Three studies advanced sepsis care across treatment and prognostication. A multicenter RCT (A2B, JAMA) found dexmedetomidine- or clonidine-based sedation did not shorten ventilation vs propofol and increased bradycardia/agitation. Two Critical Care cohorts linked innate immune biology to outcomes: plasma H3.1 nucleosomes (NETs-derived) predicted organ failure needs, and cirrhotic sepsis showed an endothelial-injury phenotype with higher AKI and mortality.
Research Themes
- Comparative-effectiveness of ICU sedation strategies in mechanically ventilated patients including septic subgroups
- Innate immunity and NETs-derived biomarkers (H3.1 nucleosomes) for risk stratification in sepsis
- Endothelial dysfunction phenotype and adverse outcomes in sepsis with pre-existing cirrhosis
Selected Articles
1. Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients: The A2B Randomized Clinical Trial.
In this pragmatic RCT across 41 UK ICUs (n=1404), neither dexmedetomidine- nor clonidine-based sedation reduced time to successful extubation vs propofol (subdistribution HR 1.09 and 1.05, respectively). Both α2-agonists increased agitation and severe bradycardia; 180-day mortality was similar, with no interaction by sepsis status.
Impact: Provides definitive comparative-effectiveness evidence for ICU sedation, informing practice where α2-agonists are widely used in septic and non-septic patients.
Clinical Implications: Propofol remains an appropriate first-line sedative for mechanically ventilated ICU patients, including those with sepsis; clinicians should weigh higher risks of agitation and bradycardia when choosing α2-agonists.
Key Findings
- No reduction in time to successful extubation with dexmedetomidine vs propofol (subdistribution HR 1.09, 95% CI 0.96-1.25; P=.20).
- No reduction with clonidine vs propofol (subdistribution HR 1.05, 95% CI 0.95-1.17; P=.34).
- Higher agitation with dexmedetomidine (RR 1.54) and clonidine (RR 1.55) vs propofol.
- Higher severe bradycardia with dexmedetomidine (RR 1.62) and clonidine (RR 1.58) vs propofol.
- Similar 180-day mortality across groups; no interaction by sepsis status.
Methodological Strengths
- Pragmatic multicenter randomized design with large sample size
- Prespecified subgroup analyses (including sepsis) and clinical trial registration
Limitations
- Open-label design with potential performance bias
- Allowance for supplemental propofol may dilute between-group differences
Future Directions: Evaluate sedation minimization strategies, hemodynamic phenotyping, and delirium-centric outcomes in septic subgroups; cost-effectiveness analyses of sedation choices.
IMPORTANCE: Whether α2-adrenergic receptor agonist-based sedation, compared with propofol-based sedation, reduces time to extubation in patients receiving mechanical ventilation in the intensive care unit (ICU) is uncertain. OBJECTIVE: To evaluate whether dexmedetomidine- or clonidine-based sedation reduces duration of mechanical ventilation compared with propofol-based sedation (usual care). DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, open-label randomized clinical trial conducted at 41 ICUs in the UK including adults who were within 48 hours of starting mechanical ventilation, were receiving propofol plus an opioid for sedation and analgesia, and were expected to require mechanical ventilation for 48 hours or longer. The median time from intubation to randomization was 21.0 (IQR, 13.2-31.3) hours. Recruitment occurred from December 2018 to October 2023; the last follow-up occurred on December 10, 2023.
2. Plasma H3.1 nucleosomes as biomarkers of infection, inflammation and organ failure.
Among 1713 ICU patients (3671 samples), baseline H3.1 nucleosomes were higher in adjudicated sepsis vs non-sepsis and correlated with SOFA. H3.1 levels were associated with DIC and AKI and strongly predicted the need for renal replacement therapy (HR 2.00 per log10 increase). Longitudinal trajectories paralleled organ failure.
Impact: Links NETs biology to clinically actionable prognostication in sepsis and critical illness, supporting H3.1 as a candidate marker for risk stratification.
Clinical Implications: H3.1 nucleosome measurement could augment early risk assessment for RRT and coagulopathy in sepsis but should be integrated with clinical and laboratory parameters rather than used as a standalone diagnostic.
Key Findings
- Baseline H3.1 nucleosomes were higher in adjudicated sepsis (740 ng/mL) vs unconfirmed sepsis (416 ng/mL) and non-sepsis (463 ng/mL) (P<0.001).
- H3.1 levels correlated with SOFA (r=0.40) and were higher in DIC and AKI and in hyperinflammatory sepsis.
- H3.1 strongly predicted need for renal replacement therapy (HR 2.00 per log10 increase), independent of mortality.
Methodological Strengths
- Large prospective ICU cohort with serial sampling and clinical adjudication of sepsis
- Standardized, validated assay for H3.1 nucleosomes and registered cohort protocol
Limitations
- Observational design limits causal inference and diagnostic specificity
- Assay availability and thresholds may limit generalizability; standalone diagnostic performance was low
Future Directions: External validation across settings, integration with multimarker models, and interventional trials targeting NETs pathways in high-H3.1 phenotypes.
BACKGROUND: Neutrophil extracellular traps (NETs) are a vital part of the innate immune response, while excessive NET formation can cause tissue damage. H3.1 nucleosomes, a component of NETs, have emerged as a potential biomarker. This study aimed to evaluate H3.1 nucleosomes in critical illness, assessing their relationship with sepsis, organ failure, inflammatory subphenotypes and outcomes. METHODS: The MARS cohort was used, comprising of consecutive Intensive Care Unit patients, with plasma samples collected on days 0, 2 and 4. H3.1 nucleosome concentrations were measured using the Nu.Q® NETs Immunoassay.
3. Identifying a unique signature of sepsis in patients with pre-existing cirrhosis.
Among 2962 septic ICU patients, 371 had cirrhosis. Cirrhosis was independently associated with higher risk of AKI (aOR 1.65) and 30-day mortality (aOR 1.38), but not ARDS. Cirrhotic sepsis showed elevated endothelial injury markers (angiopoietin-2, von Willebrand factor, soluble thrombomodulin) and lower IL-10, IL-1β, and IL-1RA.
Impact: Defines a clinically relevant endothelial dysfunction phenotype in cirrhotic sepsis tied to adverse outcomes, guiding risk stratification and mechanistic targeting.
Clinical Implications: Cirrhotic septic patients warrant heightened surveillance for kidney injury and mortality; endothelial-stabilizing strategies and tailored resuscitation may be prioritized.
Key Findings
- Cirrhosis associated with increased AKI risk (adjusted OR 1.65; 95% CI 1.21-2.26; P=0.002).
- Cirrhosis associated with higher 30-day mortality (adjusted OR 1.38; 95% CI 1.05-1.82; P=0.022).
- No difference in ARDS risk (adjusted OR 1.02; 95% CI 0.69-1.50; P=0.92).
- Higher plasma angiopoietin-2, von Willebrand factor, and soluble thrombomodulin; lower IL-10, IL-1β, and IL-1RA in cirrhosis; IL-6 similar.
Methodological Strengths
- Large prospective cohort with multivariable adjustment and predefined outcomes
- Integrated profiling of endothelial and cytokine biomarkers
Limitations
- Single-center design may limit generalizability
- Biomarker analyses performed in a subset; observational nature precludes causal inference
Future Directions: Validate the endothelial phenotype in multicenter cohorts and test endothelial-stabilizing interventions for cirrhotic sepsis; incorporate biomarkers into prognostic models.
BACKGROUND: The pre-existing diagnosis of cirrhosis is a complicating factor in the progression and prognosis of sepsis; however, the unique epidemiology, sepsis characteristics, and underlying mechanisms of immune dysregulation in sepsis among patients with cirrhosis remain incompletely understood. Our primary objective was to identify clinical outcomes and biological characteristics that differ between patients with and without cirrhosis among critically ill patients with sepsis. METHODS: We analyzed data from a prospective cohort of critically ill patients presenting to single center with sepsis.