Daily Sepsis Research Analysis

BACKGROUND: Sepsis is a common and serious condition, defined as a dysregulated host response to infection, that leads to life-threatening organ dysfunction. In emergency department settings, accurate diagnosis can be challenging, as many non-infectious conditions have similar presenting features and there is no gold standard diagnostic test, which can lead to misdirected use of antibiotics. Procalcitonin is a well characterised biomarker that responds rapidly and with high specificity to the presence of bacterial infection. We aimed to investigate whether supplementing current practice with rapid procalcitonin testing would improve recognition of sepsis and allow reduced antibiotic prescribing with at least no change in overall mortality. METHODS: A parallel, two-arm, open-label, individually randomised controlled trial was done in 20 hospital emergency departments within 17 National Health Service (NHS) Trusts or Health Boards across England and Wales. Patients aged 16 years and older with suspected sepsis were randomly assigned to either usual care or procalcitonin-guided care in a 1:1 ratio via a centrally controlled web-based randomisation programme. Participants, research staff, those assessing outcomes, and statisticians analysing the data were not masked to group assignment. Participants in the usual care group were assessed according to standard clinical management based on National Early Warning Score 2 (NEWS2). In the procalcitonin-guided care group, rapid procalcitonin testing was used in combination with NEWS2 assessment by use of a guidance-only algorithm for clinicians. This algorithm for clinical management was used for both usual care and procalcitonin-guided care groups and clinicians were free to use, ignore, or deviate from the algorithm. The co-primary endpoints were intravenous antibiotic initiation at 3 h (superiority) and 28-day mortality (non-inferiority) from triage assessment, assessed in all randomly assigned consenting participants with data for both co-primary outcomes available. Non-inferiority was concluded for 28-day mortality if the upper bound of the 90% CI was below a 2·5% margin on the risk difference scale. All patients who were randomly assigned to one of the two groups and who consented to data collection at baseline were included in adverse event analysis for the period they were included in the study. The study was registered with ISRCTN (ISRCTN54006056) and is complete. FINDINGS: Between Nov 20, 2020, and Nov 1, 2023, a total of 7667 patients were recruited and randomly assigned to the usual care group (n=3836) or the procalcitonin-guided care group (n=3831). 5453 patients (2748 female, 2703 male, 1 non-binary, 1 data for gender missing) were included in the primary analysis population (2715 usual care, 2738 procalcitonin-guided care). The last 28-day follow-up was on Nov 29, 2023. There was no difference in intravenous antibiotic initiation at 3 h from triage assessment between the two groups: 48·4% (1325/2738 participants) in the procalcitonin-guided care group versus 48·2% (1308/2715 participants) in the usual care group (adjusted risk difference -0·08 percentage points, 95% CI -2·58 to 2·42; p=0·95). Mortality at 28 days was lower in the procalcitonin-guided care group: 13·6% (372/2738 participants) in the procalcitonin-guided care group versus 16·6% (450/2715 participants) in the usual care group (adjusted risk difference -3·12 percentage points, 90% CI -4·68 to -1·57; p=0·0009). The upper bound of the 90% CI was below the non-inferiority margin of 2·5 percentage points and the point of no effect, implying both non-inferiority and superiority at the one-sided 5% level. In the primary analysis population, the procalcitonin test result was considered in clinical decision making in 64·7% (1771/2738) of participants in the procalcitonin-guided care group. Improved mortality was not explained by findings of planned subgroup, sensitivity, or secondary analyses. A total of 180 adverse events were recorded, 53·3% (96 events in 57 [1·9%] of 2968 participants) in the usual care group and 46·7% (84 events in 66 [2·2%] of 3042 participants) in the procalcitonin-guided care group. One (<1%) of 2042 participants in the procalcitonin-guided care group reported a serious adverse event probably or definitely attributable to the procalcitonin test. INTERPRETATION: Making a procalcitonin-guided algorithm available to clinicians in emergency departments did not change intravenous antibiotic initiation at 3 h in patients managed as suspected sepsis, but a decrease in 28-day mortality was seen and further research is needed to understand this finding. FUNDING: National Institute for Health and Care Research.

BACKGROUND: Many patients who survive abdominal sepsis develop Chronic Critical Illness (CCI), characterized by prolonged intensive care unit (ICU) stay, ongoing organ dysfunction, and poor one-year outcomes. Current severity scoring systems, such as SOFA and APACHE II, are not effective in identifying patients at high risk for this trajectory, limiting the opportunities for early intervention. METHODS: We conducted a prospective longitudinal study of adults diagnosed with abdominal sepsis at a tertiary acute care center. The serum levels of 13 biomarkers were measured on days 1, 4, 7, and 14 after diagnosis. Patients were grouped into two categories: Rapid Recovery (RAP) and CCI. Predictive models were developed by combining clinical data based on the Predisposition, Insult, Response, and Organ dysfunction (PIRO) framework with biomarker trends to assess the evolving host response. RESULTS: Patients with CCI showed poorer clinical outcomes than those with RAP. Among the 252 patients included in the analysis, dynamic profiling revealed significant differences between the RAP and CCI groups. Patients who developed CCI exhibited persistently elevated levels of immunosuppressive biomarkers (sPD-L1, Arg-1, and TGF-β) and inflammatory markers (IP-10), along with dysregulation of the angiogenic and metabolic pathways. Multivariate models incorporating PIRO variables showed strong performance in predicting CCI by day 4 (AUC = 0.899) and poor one-year outcomes (Zubrod 4/5) by day 7 (AUC = 0.851). The addition of key biomarkers significantly enhanced the predictive accuracy for both CCI (AUC = 0.926) and functional outcomes (AUC = 0.910). CONCLUSIONS: Our findings suggest that Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), a maladaptive pathophysiological state, plays a central role in the development of CCI following abdominal sepsis. The combination of serial biomarker data and clinical variables enables earlier and more accurate risk stratification. This approach may support timely and targeted interventions to improve patient survival and long-term recovery.

PURPOSE: One-hour sepsis bundle was developed in 2018. However, the optimal timing for antibiotic, fluid resuscitation, and vasopressor initiation in intensive care units (ICUs) remains debated. High-quality randomized evidence is limited, particularly for ICU patients. Therefore, we emulated three target trials using observational data. PATIENTS AND METHODS: We conducted a retrospective, multicenter cohort study using data from the Medical Information Mart for Intensive Care-IV database (primary dataset), and two ICU cohorts from China (Zhujiang and Xiangya hospitals). Within a target trial emulation framework with inverse probability of treatment weighting, we constructed three two-arm trials comparing initiation of (1) antibiotics, (2) fluid resuscitation, and (3) vasopressors within 0-1 hour versus 1-3 hours after a prespecified time zero. RESULTS: In the target trial emulations, antibiotic initiation within 1 hour was associated with lower 28-day mortality (HR 0.65; 95% CI 0.54-0.79) and earlier ICU discharge (competing-risk analysis; SHR 1.20; 95% CI 1.12-1.27) compared with initiation at 1-3 hours. For fluid resuscitation, initiating within 1 hour and delivering ≥30 mL/kg crystalloid within 3 hours resulted in lower mortality (HR 0.72; 95% CI 0.53-0.97) and earlier discharge (SHR 1.17; 95% CI 1.02-1.33). However, vasopressor initiation within 1 hour showed no survival benefit (HR 1.07; 95% CI 0.89-1.29) or reduction in time to ICU discharge (SHR 1.02; 95% CI 0.95-1.08). These findings remained consistent across sensitivity and subgroup analyses, including comparisons using a 1-6 hour window. CONCLUSION: In ICUs, early administration of antibiotics and initiation of fluid resuscitation within 1 hour were associated with improved survival and earlier ICU discharge, whereas early vasopressor use was not. These findings might support a bedside emphasis on timely antibiotics and fluids during early resuscitation and provide evidence for refining time targets in future sepsis guidelines.