Daily Sepsis Research Analysis
Three impactful sepsis studies stood out today: a multicenter prospective cohort identified an extracellular vesicle coagulolytic balance (EV-CLB) that independently predicts 90-day mortality in septic shock; an updated meta-analysis of RCTs found no mortality benefit of continuous versus intermittent meropenem infusion, though clinical cure and ICU length of stay improved; and a large multicenter analysis showed children with prearrest sepsis have markedly worse in-hospital cardiac arrest outco
Summary
Three impactful sepsis studies stood out today: a multicenter prospective cohort identified an extracellular vesicle coagulolytic balance (EV-CLB) that independently predicts 90-day mortality in septic shock; an updated meta-analysis of RCTs found no mortality benefit of continuous versus intermittent meropenem infusion, though clinical cure and ICU length of stay improved; and a large multicenter analysis showed children with prearrest sepsis have markedly worse in-hospital cardiac arrest outcomes without differences in intra-arrest diastolic blood pressure.
Research Themes
- Coagulation–fibrinolysis imbalance biomarkers in septic shock
- Beta-lactam dosing strategies (continuous vs intermittent infusion) in sepsis
- Pediatric sepsis and resuscitation outcomes after in-hospital cardiac arrest
Selected Articles
1. The Procoagulant and Fibrinolytic Balance of Extracellular Vesicles Predicts Mortality in Septic Shock Patients.
In a multicenter prospective cohort of 225 septic shock patients, the extracellular vesicle coagulolytic balance (EV-CLB)—the ratio of TF-dependent thrombin to uPA-dependent plasmin generation—was significantly higher in non-survivors and independently predicted 90-day mortality. EV-CLB outperformed individual EV procoagulant or fibrinolytic measures and correlated with SAPS II and lactate, with notable prognostic strength in Gram-negative and intra-abdominal/urinary infections.
Impact: Introduces a mechanistically anchored, EV-based composite biomarker with independent prognostic value in septic shock, potentially enabling phenotype-guided therapy addressing coagulation–fibrinolysis imbalance.
Clinical Implications: EV-CLB may support early risk stratification and guide individualized strategies (e.g., anticoagulation or antifibrinolytic modulation), though technical standardization of EV assays is needed before clinical adoption.
Key Findings
- EV-CLB at 24 h was higher in non-survivors vs survivors (median 2.78 vs 0.97 a.u., p<0.001).
- Survivors showed a significant EV-CLB decrease from H0 to H48, unlike non-survivors.
- EV-CLB independently predicted day-90 mortality after adjusting for severity and comorbidities.
- EV-CLB correlated better with SAPS II and lactate than individual EV procoagulant or fibrinolytic measures.
- Subgroup analyses showed strong prognostic value in peritonitis, biliary/urinary infections, and Gram-negative sepsis.
Methodological Strengths
- Multicenter prospective design with predefined primary outcome (day-90 mortality).
- Multivariable Cox modeling adjusting for severity markers and comorbidities; trial registered (NCT02062970).
Limitations
- Observational design limits causal inference regarding coagulation/fibrinolysis modulation.
- EV measurement standardization and technical complexity may impede near-term clinical translation.
Future Directions: Validate EV-CLB in external cohorts, standardize assays, and test EV-CLB–guided anticoagulation/antifibrinolytic strategies in adaptive trials.
Septic shock is characterised by abnormal coagulation activation with defective fibrinolysis, leading to a high mortality rate. Cellular activation triggers the release of extracellular vesicles (EVs) conveying both procoagulant and fibrinolytic activities. We investigated whether the balance between these activities, termed EV-coagulolytic balance (EV-CLB), predicts day-90 mortality in 225 septic shock patients included in a multicentre prospective study. EV-CLB, quantified as a ratio of TF-dependent thrombin generation to uPA-dependent plasmin generation, was higher in non-survivors than in survivors at 24 h (2.78 [0.86-16.1] a.u. vs. 0.97 [0.34-2.18] a.u., p < 0.001). Moreover, survivors showed a significant decrease in EV-CLB from H0 to H48 in contrast to non-survivors. EV-CLB was a better predictor than EV-associated-procoagulant and -fibrinolytic activities taken individually and better correlated with sepsis severity markers such as SAPS II and lactate levels. Multivariate Cox regression models including severity markers and comorbidities confirmed EV-CLB as an independent predictor of mortality in septic shock patients. Interestingly, subgroup analysis revealed EV-CLB's strong prognostic value in peritonitis, biliary and urinary tract infections and Gram-negative sepsis. Despite challenges in EV measurement requiring technical advancement for clinical translation, EV-CLB represents a potential novel biomarker to guide individualised therapy targeting coagulation/fibrinolysis imbalance in septic shock. Trial Registration: This trial was registered at ClinicalTrials.gov identifier: NCT02062970.
2. Continuous vs. intermittent meropenem infusion in critically ill patients with sepsis: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.
Across five RCTs (n=1,075), continuous meropenem infusion did not reduce all-cause mortality versus intermittent dosing (RR 0.89, 95% CI 0.75–1.04) but was associated with shorter ICU length of stay, higher clinical cure rates, and shorter meropenem duration. Findings refine dose–administration strategies by highlighting a lack of survival benefit while suggesting potential workflow or PK/PD advantages.
Impact: Provides updated, RCT-only evidence with trial sequential analysis, correcting earlier impressions of survival benefit from continuous infusion and guiding antibiotic administration policies.
Clinical Implications: Intermittent meropenem dosing remains appropriate when targeting mortality endpoints; continuous infusion may be reserved for PK/PD optimization or resource considerations given improved cure and ICU LOS but requires individualized assessment.
Key Findings
- Five RCTs (n=1,075) showed no mortality reduction with continuous infusion vs intermittent dosing (RR 0.89; 95% CI 0.75–1.04).
- Continuous infusion was associated with shorter ICU length of stay.
- Higher clinical cure rates and shorter meropenem therapy duration were observed with continuous infusion.
- Trial sequential analysis supports the conclusion of no mortality benefit to date.
Methodological Strengths
- Meta-analysis restricted to randomized controlled trials with trial sequential analysis.
- Pre-registered systematic review (PROSPERO CRD42024528380) and multi-database search.
Limitations
- Heterogeneity in dosing regimens and infusion protocols across RCTs.
- Mortality may be underpowered for subgroup effects; limited number of trials.
Future Directions: Large pragmatic RCTs focusing on high MIC pathogens and PK/PD target attainment, with patient-centered outcomes (mortality, organ support-free days).
BACKGROUND: A recent large multicenter randomized controlled trial (RCT) found that continuous infusion (CI) of meropenem did not improve clinical outcomes in critically ill patients, contradicting previous meta-analysis results. METHODS: We conducted a search of the PubMed, EMBASE, and Cochrane databases up to March 19, 2024. RESULTS: Our study included a total of 1,075 critically ill patients with sepsis from five RCTs. The primary outcome indicated that CI of meropenem did not reduce all-cause mortality in patients (RR = 0.89; 95% CI, 0.75-1.04; CONCLUSION: In critically ill patients with sepsis, CI of meropenem did not reduce mortality but was associated with shorter ICU length of stays, higher clinical cure rates, and shorter duration of meropenem therapy. Further large-scale RCTs are needed to validate these findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024528380, identifier CRD42024528380.
3. Outcomes, Characteristics, and Physiology of In-Hospital Cardiac Arrest in Children With Sepsis.
Among 1,129 pediatric IHCAs, prearrest sepsis (16.3%) was associated with markedly reduced survival to discharge with favorable neurologic outcome (28.3% vs 58.4%; adjusted RR 0.54, 95% CI 0.43–0.68). Despite worse outcomes and higher vasoactive needs, intra-arrest diastolic blood pressures were similar between sepsis and non-sepsis groups.
Impact: Provides multicenter, adjusted evidence that pediatric sepsis dramatically worsens IHCA outcomes without differences in intra-arrest DBP, informing prevention, resuscitation planning, and postarrest care priorities.
Clinical Implications: Children with prearrest sepsis represent a high-risk IHCA phenotype warranting aggressive prevention, early deterioration detection, and enhanced postarrest hemodynamic support; DBP targets during CPR may not need sepsis-specific modification.
Key Findings
- Prearrest sepsis present in 16.3% (184/1129) of pediatric IHCAs.
- Favorable neurologic survival markedly lower with sepsis (28.3% vs 58.4%; adjusted RR 0.54, 95% CI 0.43–0.68).
- Sepsis patients had longer CPR durations and more frequent epinephrine and bicarbonate use.
- Average diastolic blood pressure during CPR did not differ between sepsis and non-sepsis groups.
- Postarrest, sepsis survivors had higher vasoactive requirements, more hypotension, and higher early mortality.
Methodological Strengths
- Large multicenter cohort with prospectively designed data capture and adjusted analyses.
- Clinically meaningful outcomes including favorable neurologic survival and intra-arrest physiology.
Limitations
- Secondary analysis; exposure to sepsis was not randomized and residual confounding is possible.
- Lack of granular infection source/pathogen data to explain physiologic differences.
Future Directions: Develop sepsis-specific IHCA prevention bundles and test postarrest hemodynamic strategies in randomized or adaptive trials for this high-risk phenotype.
OBJECTIVES: Prearrest sepsis has been associated with particularly poor outcomes among children who suffer in-hospital cardiac arrest (IHCA), but there is a paucity of dedicated studies on the topic. In this study of children receiving cardiopulmonary resuscitation (CPR) in the ICU, our objective was to determine the associations of sepsis with IHCA outcomes and intraarrest physiology. DESIGN: Prospectively designed secondary analysis of the ICU Resuscitation Project clinical trial (NCT02837497). SETTING: The 18 pediatric and pediatric cardiac ICUs at ten children's hospitals in the United States. PATIENTS: Children (≤ 18 yr) with an index IHCA event. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was a prearrest diagnosis of sepsis. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was average diastolic blood pressure (DBP) during CPR. Multivariable regression models controlling for a priori covariates assessed the relationship between sepsis and outcomes. Of 1129 children with index IHCAs, 184 (16.3%) had prearrest sepsis. Patients with sepsis had greater prearrest comorbidities, higher prearrest severity of illness, and higher Vasoactive-Inotropic Scores than patients without sepsis. They more frequently had hypotension as the cause of IHCA, had longer durations of CPR, and more frequently received epinephrine and sodium bicarbonate during CPR. They less frequently achieved survival with favorable neurologic outcome (52/184 [28.3%] vs. 552/945 [58.4%]; p < 0.001; adjusted relative risk, 0.54; 95% CI, 0.43-0.68; p < 0.001). Intraarrest DBPs did not differ between patients with vs. without sepsis. Following IHCA, event survivors with sepsis had higher vasoactive requirements, more frequently experienced hypotension, and continued to have greater mortality rates through 48 hours postarrest. CONCLUSIONS: Children with prearrest sepsis had worse survival outcomes, similar intraarrest DBPs, and greater pre and postarrest severity of illness than children without sepsis.