Daily Sepsis Research Analysis
Three studies advance sepsis science across clinical risk stratification, infection management, and mechanistic therapeutics. Temperature trajectory phenotypes in ED sepsis patients identify a hypothermic, high-mortality subgroup; ICU candidemia data quantify secondary localization risk and management impact; and a CLP model links tempol’s organ protection to Klotho upregulation, highlighting a redox–antiinflammatory therapeutic axis.
Summary
Three studies advance sepsis science across clinical risk stratification, infection management, and mechanistic therapeutics. Temperature trajectory phenotypes in ED sepsis patients identify a hypothermic, high-mortality subgroup; ICU candidemia data quantify secondary localization risk and management impact; and a CLP model links tempol’s organ protection to Klotho upregulation, highlighting a redox–antiinflammatory therapeutic axis.
Research Themes
- Physiologic trajectory-based risk stratification in sepsis
- Management of ICU candidemia and secondary localization risk
- Mechanistic therapeutics targeting oxidative stress/Klotho in sepsis
Selected Articles
1. Screening, prevalence, and risk factors for secondary localization during candidemia in intensive care unit patients: the French CandidICU multicenter study.
In 16 French ICUs, 21.8% of candidemia patients had at least one secondary localization. Higher SAPS II scores and longer duration of positive blood cultures independently increased SL risk, while older age and Candida glabrata infection were protective; SL led to longer antifungal courses and more escalation.
Impact: Provides actionable risk stratification for secondary foci in ICU candidemia and demonstrates attendant changes in antifungal management.
Clinical Implications: Prioritize comprehensive SL screening (e.g., echocardiography, ophthalmology) in patients with high SAPS II or prolonged positive cultures, and anticipate longer therapy/escalation; consider de-escalation in lower-risk phenotypes.
Key Findings
- Secondary localization (SL) was diagnosed in 21.8% of ICU candidemia patients; 76.4% were screened.
- Higher SAPS II and longer duration of positive blood cultures independently increased SL risk (sdHR 1.01 and 1.05, respectively).
- Older age and Candida glabrata infection were protective (sdHR 0.98 and 0.38).
- SL was associated with longer antifungal treatment (median 18 vs 14 days) and higher escalation rates (27.8% vs 12.3%).
Methodological Strengths
- Multicenter ICU cohort with 492 candidemia cases across 16 centers
- Competing risk analysis to identify independent risk factors
Limitations
- Retrospective design with potential selection bias; only 76.4% underwent screening
- Causality cannot be inferred; details on SL sites and standardized screening protocols may vary
Future Directions: Prospective standardized SL screening pathways and external validation to refine risk-based resource allocation and antifungal strategies.
BACKGROUND: Candidemia is a life-threatening fungal infection in intensive care unit (ICU) patients that can be complicated by secondary localization (SL). However, the prevalence, risk-factors, and outcomes of patients with secondary localization during candidemia remain poorly explored. METHODS: The CandidICU study was a retrospective multicenter cohort study conducted in 16 French ICUs. All adult patients hospitalized from 01-2015 to 01-2023 for candidemia were enrolled. We assessed the prevalence and risk-factors for SL. In addition, we explored the clinical course according to the screening and occurrence of SL. RESULTS: Among 492 patients hospitalized in ICU with at least one positive blood culture for Candida sp., 376 were screened for SL (76.4%). At least one SL was diagnosed in 82 patients (21.8%). Competing risk analysis identified the SAPSII score and the duration of positive blood cultures as independent risk factors for SL (sdHR 1.01 [95%CI 1.00-1.02]; p = 0.031 and sdHR 1.05 [95%CI 1.02-1.08]; p = 0.003, respectively). Age and Candida glabrata infection were protective factors against SL (sdHR 0.98 [95%CI 0.97-1.00]; p = 0.016 and sdHR 0.38 [95%CI 0.15-0.99]; p = 0.048, respectively). Finally, patients with SL received longer antifungal treatment (18 [11-30] versus 14 [6-18] days; p < 0.001) and had a higher rate of antifungal escalation (27.8% versus 12.3%; p = 0.002). CONCLUSIONS: In this cohort, 76·4% of ICU patients with candidemia were screened for SL and at least one SL was diagnosed in 21·8%. The severity at ICU admission and duration of positive blood cultures were identified as independent risk factors for SL, whereas age and Candida glabrata infection were protective. Finally, the screening and occurrence of SL were associated with significant changes in the management of patients.
2. Exploring temperature trajectories in emergency department sepsis patients.
Using MIMIC-IV data, four temperature trajectories were identified in ED sepsis patients, with a small hypothermic subgroup (0.9%) exhibiting the highest mortality (37.5%). Normothermic and fever-related trajectories had substantially lower mortality, supporting trajectory-informed risk assessment.
Impact: Highlights a physiologic phenotype—hypothermia—with markedly elevated mortality, enabling early ED risk stratification beyond single temperature thresholds.
Clinical Implications: Incorporate temperature trajectory phenotyping into sepsis triage and monitoring to flag hypothermic patients for aggressive resuscitation and closer observation.
Key Findings
- Four temperature trajectories were identified: Hypothermic (0.9%), Normothermic (74.1%), Progressive Fever (10.7%), and Fever Resolver (14.4%).
- The Hypothermic group had the highest mortality (37.5%), significantly exceeding other groups (p < 0.001).
- Group-based trajectory modeling with derivation and replication cohorts demonstrated consistent patterns.
Methodological Strengths
- Large retrospective cohort with derivation (n=3872) and replication (n=1660)
- Group-based trajectory modeling with BIC-guided model selection
Limitations
- Retrospective single-database study with potential unmeasured confounding
- Temperature measurement frequency and methods may vary; lacks prospective external validation
Future Directions: Prospective validation and integration with multimodal physiologic trajectories to guide ED sepsis pathways and resuscitation targets.
INTRODUCTION: Sepsis presents a global challenge to emergency departments (ED) due to its varied presentation and life-threatening outcomes. The quick Sequential Organ Failure Assessment score's introduction expanded sepsis diagnostics beyond the traditional Systemic Inflammatory Response Syndrome, which considered body temperature. However, body temperature remains a vital clinical marker. This study analyzes body temperature patterns in ED sepsis patients and their impact on treatment and outcomes. METHODS: This retrospective cohort study analyzed the data from the MIMIC-IV database, focusing on sepsis patients diagnosed within 12 h of ED triage. Patients were split into derivation (n = 3872) and replication (n = 1660) cohorts in a 7:3 ratio and categorized into body temperature trajectory subgroups using group-based trajectory modeling. The model's effectiveness was assessed using the Bayesian Information Criterion, with validation in a replication cohort. Analysis of variance and chi-squared tests were used to evaluate patient characteristics and outcomes. RESULTS: Four distinct body temperature patterns were identified: Hypothermic (0.9 %), Normothermic (74.1 %), Progressive Fever (10.7 %), and Fever Resolver (14.4 %). The Hypothermic group had the highest mortality rate (37.5 %), while the Normothermic, Progressive Fever, and Fever Resolver groups had mortality rates of 11.7 %, 9.14 %, and 9.78 %, respectively (p < 0.001). CONCLUSIONS: Fever is not always a reliable sepsis indicator; many patients present normothermic or hypothermic, notably the highest mortality cohort. Including diverse temperature patterns in sepsis assessments could enhance patient outcomes.
3. Klotho modulation by tempol: a potential therapeutic axis in sepsis.
In a CLP sepsis model, tempol improved survival and cardiorenal function while decreasing IL-6, lactate, p38, TNF-α, and caspase-3, and increasing GSH, SOD, and Klotho expression. Findings support a Klotho-centered redox–inflammation axis as a therapeutic target.
Impact: Offers mechanistic evidence linking tempol’s antioxidant action to Klotho upregulation, providing a plausible therapeutic axis for sepsis-induced organ injury.
Clinical Implications: Suggests evaluating tempol or Klotho-enhancing strategies in early-phase clinical trials for septic cardiorenal protection; underscores monitoring of oxidative and inflammatory biomarkers.
Key Findings
- Tempol improved survival and cardiorenal function in CLP-induced sepsis.
- Tempol reduced IL-6 and lactate levels and corrected oxidant/antioxidant imbalance.
- Klotho expression increased with tempol, while p38, TNF-α, and caspase-3 expression decreased.
- Antioxidant defenses (GSH, SOD) were elevated by tempol treatment.
Methodological Strengths
- Use of the CLP model, a clinically relevant polymicrobial sepsis paradigm
- Multidomain assessment (survival, histology, functional and molecular readouts)
Limitations
- Preclinical animal study; human translatability uncertain
- Dose–response, timing optimization, and necessity of Klotho not genetically validated
Future Directions: Test Klotho-dependence (e.g., Klotho knockdown/knockout) and evaluate tempol in large-animal models and early clinical trials with biomarker-guided endpoints.
BACKGROUND: Sepsis is characterized by massive inflammatory and oxidative stress responses. The imbalance between oxidant and antioxidant activities during sepsis contributes to hyperinflammation, oxidation, endothelin system activation, and apoptosis, key elements of multiorgan failure. The current study investigated the role of tempol attenuating sepsis-induced acute cardiorenal injuries through modulation of Klotho. METHOD: We used a cecal ligation and puncture (CLP) model of sepsis. Survival rate, histopathological assessment, and cardiorenal functions were analyzed. Oxidant and antioxidant activities, IL-6, and lactate were measured. The expression of tumor necrosis factor- α (TNF-α), p38-mitogen activating protein kinase (p38-MAPK), klotho, and caspase-3 were evaluated by immunohistochemistry. RESULTS: CLP caused acute cardiorenal damage, high mortality, upregulated levels of IL-6 and lactate, an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3, and reduced expression of klotho. Tempol improved survival, reduced inflammatory and oxidative stress parameters, improved cardiorenal functions, elevated the tissue contents of reduced glutathione (GSH) and superoxide dismutase (SOD), raised the expression of klotho protein and reduced the expression of p38, TNF- α and caspase-3. CONCLUSION: Tempol is a promising agent against sepsis-induced organ damage. This was evident in its cardiorenal protective effect, up-regulation of klotho, suppression of inflammation, oxidation, and apoptosis, and enhancement of the antioxidant status.