Daily Sepsis Research Analysis
Three studies stand out today in sepsis research: a large multicenter cohort links faster achievement of full enteral feeds to reduced late-onset sepsis and necrotizing enterocolitis in extremely preterm infants; a double-blind RCT suggests norepinephrine may lower additional vasopressor needs and improve in-hospital survival versus dopamine in preterm septic shock; and a prospective study proposes a combined antithrombin/activated protein C model that improves early detection of non-overt DIC a
Summary
Three studies stand out today in sepsis research: a large multicenter cohort links faster achievement of full enteral feeds to reduced late-onset sepsis and necrotizing enterocolitis in extremely preterm infants; a double-blind RCT suggests norepinephrine may lower additional vasopressor needs and improve in-hospital survival versus dopamine in preterm septic shock; and a prospective study proposes a combined antithrombin/activated protein C model that improves early detection of non-overt DIC and predicts mortality in pneumonia-related sepsis.
Research Themes
- Nutrition-driven prevention of neonatal sepsis and NEC
- Vasopressor selection in preterm septic shock
- Early coagulation phenotyping to anticipate DIC and mortality
Selected Articles
1. Time to Full Enteral Feeds and Late-Onset Sepsis in Extremely Preterm Infants.
In 15,102 extremely preterm infants across 19 US centers, each 1-week delay in achieving full enteral feeding was associated with a 16% higher risk of late-onset sepsis (ARR 1.16, 95% CI 1.14–1.18). Delays were also linked to higher risks of necrotizing enterocolitis and growth faltering in weight, length, and head circumference. Over time, median days to full feeds decreased (18→14), paralleling a reduction in late-onset sepsis (21.1%→16.5%).
Impact: Large, contemporary multicenter data provide robust evidence linking feeding advancement speed to sepsis risk and other key neonatal outcomes, informing modifiable care practices in extremely preterm infants.
Clinical Implications: Implement protocols that safely accelerate advancement to full enteral feeds in extremely preterm infants to reduce late-onset sepsis, NEC, and growth faltering, with careful monitoring for feeding tolerance.
Key Findings
- Each 1-week delay to full enteral feeds increased late-onset sepsis risk by 16% (ARR 1.16, 95% CI 1.14–1.18, P<.001).
- Delays were associated with higher NEC risk (ARR 1.20, 95% CI 1.16–1.24) and growth faltering in weight, length, and head circumference.
- Over 2012–2021, time to full feeds decreased (18→14 days) alongside reduced late-onset sepsis incidence (21.1%→16.5%, P=.003).
Methodological Strengths
- Large multicenter cohort (N=15,102) with decade-long contemporary data
- Adjusted analyses accounting for illness severity and birth year, with predefined outcomes
Limitations
- Observational design limits causal inference and residual confounding may persist
- Selection limited to infants surviving beyond day 7; feeding protocols may vary across centers
Future Directions: Prospective interventional trials to test structured rapid feeding advancement protocols and evaluate safety, individualized by risk profiles.
IMPORTANCE: Recent studies suggest that early achievement of full enteral feeding improves clinical outcomes among preterm infants. OBJECTIVE: To examine the association between full enteral feeding and late-onset sepsis. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a cohort study prospectively followed up a multicenter cohort of preterm infants with gestational ages ranging from 23 to 28 weeks born between January 1, 2012, and December 31, 2021, at 19 US academic centers. Infants without major anomalies who received enteral feedings and survived bey
2. Dopamine versus norepinephrine in fluid-refractory septic shock among preterm neonates: a double-blind randomized controlled trial.
In a double-blind RCT of 50 preterm neonates with fluid-refractory septic shock, early reversal within 45 minutes was not significantly different between norepinephrine and dopamine. However, norepinephrine reduced the need for additional vasoactive agents (33.3% vs 61.5%) and showed improved in-hospital survival by time-to-event analysis.
Impact: Provides randomized, blinded comparative data in a vulnerable population where high-quality trials are scarce, informing vasopressor selection in preterm neonatal septic shock.
Clinical Implications: Consider norepinephrine as first-line vasopressor for fluid-refractory septic shock in preterm neonates given reduced need for additional agents and survival signals, while acknowledging the small sample and need for larger trials.
Key Findings
- Early reversal within 45 minutes: 62.5% with norepinephrine vs 42.3% with dopamine (RR 0.677; 95% CI 0.392–1.168; not significant).
- Fewer required additional vasoactive drugs with norepinephrine (33.3%) vs dopamine (61.5%) (RR 1.846; 95% CI 1.000–3.509; P=.04).
- Time-to-event analysis indicated improved in-hospital survival with norepinephrine (HR 1.66; 95% CI 1.12–2.45; P=.01).
Methodological Strengths
- Double-blind randomized controlled design in a neonatal ICU setting
- Standardized dosing ranges for both vasopressors with predefined primary and secondary outcomes
Limitations
- Small single-center sample may be underpowered for mortality and primary endpoint differences
- Short early reversal window (45 minutes) may not capture longer hemodynamic effects
Future Directions: Multicenter RCTs to validate norepinephrine superiority or non-inferiority, assess dose-response, and evaluate longer-term neurodevelopmental outcomes.
The present study aims to compare the efficacy and safety of norepinephrine (NE) versus dopamine in achieving early (within 45 min of initiation) reversal of fluid-refractory septic shock in preterm neonates. A double-blind randomized controlled trial was conducted in a Level-III tertiary care hospital in Northern India. Fifty neonates born at a gestational age of <37 weeks and diagnosed with fluid-refractory septic shock till 28 days of life were randomly allocated to receive either dopamine infusion (10-20 μg/kg/min) or NE infusion (0.2-0.4 μg/kg/min). We found that the proportion of preterm neonates achieving early (within 45 min of initiation) reversal of septic shock was 11/26 (42.3%) in the dopamine group vs. 15/24 (62.5%) in the NE group, respectively [risk ratio (RR) 0.677; 95% confidence interval (CI) 0.392-1.168]. Among secondary outcomes, the proportion of neonates requiring additional vasoactive drugs was significantly less in the NE group, 8/24 (33.3%) vs. the dopamine group, 16/26 (61.5%), respectively (RR 1.846; 95% CI 1.000-3.509, P=.04). Additionally, the probability of requiring additional vasoactive drugs and remaining alive during the hospital stay were significantly higher in the NE group [hazard ratio (HR) 1.66; 95% CI 1.12-2.45, P=.01 by log-rank test]. There was no significant difference in other clinical outcomes. Among preterm neonates with fluid-refractory septic shock, NE (0.2-0.4 μg/kg/min) and dopamine (10-20 μg/kg/min) had comparable efficacy and safety.
3. Superiority of a combined antithrombin and activated protein C model for predicting coagulopathy and mortality in pneumonia-related sepsis: A prospective cohort study.
In 86 adults with severe pneumonia-related sepsis, lower antithrombin and higher activated protein C at enrollment were associated with mortality and DIC progression. A combined AT/aPC model improved prediction of 28-day mortality (AUC 0.814) and uniquely identified non-overt DIC (AUC 0.850), outperforming either biomarker alone.
Impact: Proposes a simple two-biomarker approach to detect early coagulopathy and stratify mortality risk in pneumonia-related sepsis, addressing limitations of ISTH criteria.
Clinical Implications: Early AT/aPC testing may guide intensified monitoring and consideration of anticoagulation strategies in high-risk pneumonia sepsis, especially at the non-overt DIC stage.
Key Findings
- 28-day mortality was 26.7%; 20.9% developed overt DIC within 72 hours.
- Non-survivors had lower AT activity (median 65% vs 78%; P=0.005) and higher aPC (127 vs 93.9 pg/mL; P<0.001).
- AT/aPC combined model predicted mortality (AUC 0.814) and identified non-overt DIC (AUC 0.850), outperforming AT or aPC alone.
Methodological Strengths
- Prospective cohort design with a priori biomarker measurement and ROC-based evaluation
- Clinically meaningful endpoints (72-hour DIC progression and 28-day mortality)
Limitations
- Single-center, small sample size limits generalizability and precision of cutoff values
- Focus on pneumonia-related sepsis may not extrapolate to other sepsis etiologies
Future Directions: External validation in larger multicenter cohorts, determination of clinically actionable thresholds, and trials of biomarker-guided anticoagulation strategies.
BACKGROUND: Pneumonia-related sepsis is frequently complicated by coagulation disorders, which significantly increase mortality risk. The current ISTH criteria demonstrate limited sensitivity in diagnosing pneumonia-specific coagulopathy, and the mechanisms underlying clinical phenotypic heterogeneity remain poorly understood. There is a growing need to identify novel biomarkers that can enhance the early detection and stratification of disseminated intravascular coagulation (DIC), particularly in its non-overt stages. AIMS: The study aimed to evaluate the prognostic value of antithrombin (AT) and activated protein C (aPC) testing for predicting clinical deterioration and early DIC progression in adults with severe pneumonia-related sepsis. METHODS: We conducted a prospective observational cohort study of 86 adults with severe pneumonia-related sepsis admitted to the Intensive Care Unit (ICU). All patients underwent testing of AT and aPC upon enrollment. The predictive value of this biomarker combination was evaluated for the development of overt DIC within 72 h and 28-day all-cause mortality using receiver operating characteristic (ROC) analysis. RESULTS: Among 86 adults with severe pneumonia-related sepsis (median age 65 years; 56.9 % male), 18 (20.9 %) progressed to overt DIC within 72 h, and the 28-day mortality rate was 26.7 % (23/86). Compared with survivors, non-survivors exhibited significantly lower antithrombin activity (median 65 % vs. 78 %; P = 0.005) and higher activated protein C levels (median 127 pg/mL vs. 93.9 pg/mL; P < 0.001). Notably, the presence of overt DIC was the strongest predictor of mortality (OR = 144, 95 % CI: 18.66-1111.07). Similarly, patients with overt DIC exhibited markedly elevated aPC (P < 0.001). Among non-survivors, aPC was positively correlated with the 24-hour vasoactive-inotropic score (VIS; r = 0.567, P = 0.005). ROC analysis revealed that for predicting mortality, both aPC (AUC = 0.804, 95 % CI: 0.709-0.900) and the combined AT/aPC model (AUC = 0.814, 95 % CI: 0.714-0.913) significantly outperformed AT alone (AUC = 0.736, 95 % CI: 0.595-0.878).For predicting overt DIC, aPC (AUC = 0.859, 95 % CI: 0.778-0.939) and the combined model (AUC = 0.850, 95 % CI: 0.764-0.935) both demonstrated high accuracy. Notably, only the combined model effectively identified non-overt DIC (AUC = 0.850, 95 % CI: 0.768-0.932), whereas AT (AUC = 0.723) and aPC (AUC = 0.742) alone showed suboptimal performance. CONCLUSION: In conclusion, this preliminary study identifies a combined AT/aPC model as a promising early predictor of DIC progression and mortality in pneumonia-sepsis. If validated in larger, multicentre cohorts, this simple two-biomarker approach provides a potential biomarker foundation for future studies investigating personalised anticoagulation strategies by identifying high-risk patients in the non-overt DIC stage.