Daily Sepsis Research Analysis

OBJECTIVES: While general agreement exists on many sepsis management principles, the details of early fluid resuscitation in sepsis remain contentious. The aim of the current review is to examine the impact of early (≤ 8 hr) fluid dosing, timing, and guideline-based resuscitation on mortality in sepsis. DATA SOURCES: PubMed, Scopus, Cochrane, and Google Scholar from January 1, 2000, to November 8, 2024. STUDY SELECTION: Randomized controlled trials and observational data, adjusting for confounding, for adults (≥ 18 yr) with sepsis. DATA EXTRACTION: From 2,169 citations, 30 studies with 119,583 patients were included. DATA SYNTHESIS: Dosing: three randomized trials suggest no mortality difference between more liberal (~43-72 mL/kg) vs. more restrictive (as low as 30 mL/kg) fluid resuscitative strategies (relative risk, 1.00 [0.81-1.24]). Eleven of 13 studies observed mortality risk when low-fluid volumes were administered (< 20 mL/kg; effect direction/sign test: p < 0.001). Six of 11 studies observed mortality risk when fluid volume dosing exceeded higher limits (> 45 mL/kg; p = 0.55). Timing: four of four studies observed a survival benefit with earlier completion of 30 mL/kg (within 3 hr; p = 0.12). Thirty mL/kg by discrete time: less than or equal to 1 and less than or equal to 2 hours-two studies observed survival benefit; less than or equal to 3 hours-one study observed survival benefit and three studies observed no mortality impact; and less than or equal to 6 hours-two studies observed a survival benefit, four studies observed no impact, and two studies observed increased mortality risk (both > 30 groups received > 50 and > 70 mL/kg). CONCLUSIONS: For fluid resuscitation within 8 hours of sepsis diagnosis: 1) randomized trials suggest no mortality difference between more restrictive and more liberal fluid resuscitative strategies (certainty of evidence: low); 2) dosing less than 20 mL/kg has an effect on increased mortality (low certainty); 3) observational studies trend toward increased mortality with higher volume resuscitation (> 45 mL/kg) but are not supported by randomized trials (very low certainty); and 4) survival benefit is observed when 30 mL/kg is completed within 3 hours (low certainty).

OBJECTIVES: Latent class assignment-derived subphenotyping algorithms may identify treatment-responsive subgroups of critically ill patients with sepsis and acute respiratory distress syndrome. It is unclear if these algorithms are generalizable to patients with comorbid malignancy, a state which may perturb influential inflammatory biomarkers. This study aimed to test whether malignancy or neutropenia modified the effect of subphenotype assignment by two algorithms as applied to a prospective cohort enriched for ICU patients with active malignancy. DESIGN: Prospective cohort study at a single U.S. quaternary referral center. SETTING/PATIENTS: ICU patients older than 18 admitted to an ICU with a primary admission indication of sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied two published subphenotyping algorithms utilizing either interleukin (IL)-6 or IL-8 (in addition to soluble tumor necrosis factor receptor 1 and bicarbonate) to our cohort of 930 patients with sepsis, 396 (42%) of whom had active malignancy. A greater proportion of hematologic malignancy patients were assigned the "hyperinflammatory" subphenotype by the IL-8-utilizing algorithm than the IL-6 algorithm (58% vs. 32%). Patients with leukemia and neutropenia were overrepresented among those classified as hyperinflammatory by IL-8 algorithm. We constructed Cox proportional hazards models to assess for interaction between the presence of solid malignancy, hematologic malignancy, and severe neutropenia and the subphenotype/mortality association. Hematologic malignancy uniquely appeared to attenuate the associated mortality of the IL-6-assigned hyperinflammatory subphenotype (interaction; p = 0.037), but not the IL-8-assigned hyperinflammatory subphenotype (interaction; p = 0.260), which retained an independent association with mortality in hematologic malignancy subjects (hazard ratio, 1.50; 95% CI, 1.08-2.07; p = 0.014). CONCLUSIONS: As subphenotyping algorithms are being tested as point-of-care prognostic tools, it is important to understand their generalizability to patients with comorbid malignancy, which constitute an increasing proportion of ICU patients. The differential behavior of these algorithms in patients with hematologic malignancy suggests a need for independent derivation and validation in this specific population.

OBJECTIVES: Sepsis-associated acute kidney injury (SAKI) is a heterogeneous syndrome associated with poor outcomes. Subphenotypes of SAKI with prognostic and therapeutic relevance have been identified in adults, but not in children. We sought to identify reproducible and clinically relevant pediatric SAKI (pSAKI) subphenotypes using readily available clinical and laboratory data. DESIGN: Secondary analysis of a retrospective observational study of pediatric sepsis. SETTING: Thirteen PICUs in the United States from January 2012 to January 2018. PATIENTS: Patients aged 0-18 years with septic shock (sepsis and requiring vasoactive medications) and day 1-2 SAKI (≥ Kidney Disease Improving Global Outcomes stage 1 by serum creatinine). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fourteen hundred fifty-five patients were included after inclusion and exclusion criteria were applied: 873 (60%) in the derivation cohort and 582 (40%) in the external validation cohort. A two-subphenotype latent class analysis model had the best fit in both cohorts: pSAKI subphenotype 1 (pSAKI-1) and pSAKI subphenotype 2 (pSAKI-2). pSAKI-2 was characterized by younger age, more organ support, greater fluid accumulation, and laboratory evidence of inflammation, acid-base derangement, thrombocytopenia, and coagulopathy. pSAKI-2 had uniformly worse outcomes, including higher rates of severe and persistent AKI at days 3-4 (54% vs. 23%, p < 0.001) and day 7 (31% vs. 12%, p < 0.001), increased use of continuous renal replacement therapy (21% vs. 6%, p < 0.001), and independently increased odds of mortality after adjustment for potential confounders (adjusted odds ratio 1.59; 95% CI, 1.04-2.41; p = 0.03). A parsimonious classification model accurately identified pSAKI-2 membership (C-statistic 0.94 [95% CI, 0.92-0.95] and 0.85 [95% CI, 0.82-0.88], respectively, in the derivation and internal validation cohorts). CONCLUSIONS: We identified two distinct early pSAKI subphenotypes using readily available data that exhibit differential risk for poor outcomes and can be identified from a parsimonious set of variables. Pending external validation, operationalization of pSAKI subphenotypes may allow for prognostic enrichment to guide clinical care and inform clinical trial enrollment.