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Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced...
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Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions

A Special Issue of Medical Sciences (ISSN 2076-3271).

Deadline for manuscript submissions: 31 December 2026 | Viewed by 5454

Editors

Prof. Dr. Antonio Artigas

E-Mail Website
Guest Editor
Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), CIBERES, Corporació Sanitària Universitària Parc Taulí, 08208 Sabadell, Spain
Interests: critical care; sepsis; respiratory diseases; acute respiratory failure; acute lung injury
Prof. Dr. Evangelos Giamarellos-Bourboulis

E-Mail Website
Guest Editor
4th Department of Internal Medicine, ATTIKON University Hospital, 12462 Athens, Greece
Interests: sepsis; immunology; infectious diseases; pathogenesis
Dr. Adrian Ceccato

E-Mail Website1 Website2
Guest Editor
1. Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain
2. CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 41092 Madrid, Spain
Interests: pulmonary medicine; lung diseases; respiration disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Medical Sciences has created a Special Issue on Sepsis Management and Therapeutic Strategies, aiming to help clinicians with Early Recognition and to indicate New additional Interventions to improve outcomes. The last few decades have seen enormous progress in supportive therapy for sepsis to compensate for failing organs, with concomitant crucial mechanistic biological aspects of pathophysiology. Huge technological developments, such as omics associated with cellular function assessment, have led to a better understanding and the proposal of different adjuvant therapeutic strategies and a more personalized treatment. From the clinical point of view, the time is coming for the clinicians to integrate the most important concepts and therapies in our routine practice. To do so, clarification of the major aspects such as coagulation, interactions between cells and endothelial cells, immune response with the time-impact on the cell function and mediator release becomes essential for patients. The concomitant development of artificial intelligence has popularized new approaches for diagnosis and therapies. This collection will invite experts to review the essential elements from early detection, bridging the gap between public perception and clinical urgency and defining guidelines and early warning scores for the prompt identification and treatment of sepsis in health care systems.

Prof. Dr. Antonio Artigas
Prof. Dr. Evangelos Giamarellos-Bourboulis
Dr. Adrian Ceccato
Guest Editors

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Keywords

  • sepsis management
  • therapeutic strategies
  • early recognition
  • adjuvant therapies
  • omics and cellular function
  • personalized treatment
  • immune response
  • artificial intelligence in sepsis

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Published Papers (6 papers)

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Research

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16 pages, 5892 KB  
Article
Inhibition of eCIRP Attenuates Inflammation and Gut Injury After Radiation Combined Injury with Sepsis
by Fangming Zhang, Gaifeng Ma, Hui Jin, Asha Jacob, Max Brenner and Ping Wang
Med. Sci. 2026, 14(5), 539; https://doi.org/10.3390/medsci14050539 - 1 Sep 2026
Viewed by 347
Abstract
Background: Radiation-induced sepsis resulting from intestinal inflammation and injury is a severe complication of high-dose radiation exposure. High-dose radiation compromises the integrity of the intestinal lining, causing bacterial translocation, systemic inflammation, and sepsis. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, plays [...] Read more.
Background: Radiation-induced sepsis resulting from intestinal inflammation and injury is a severe complication of high-dose radiation exposure. High-dose radiation compromises the integrity of the intestinal lining, causing bacterial translocation, systemic inflammation, and sepsis. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, plays a pivotal role in the pathogenesis of inflammatory diseases and contributes to organ injury. C23, a small molecular peptide antagonist of eCIRP, has demonstrated anti-inflammatory and organ-protective effects during organ-injury indications. However, its role in radiation-induced inflammation and injury is not known. The objective of this study is to evaluate whether C23 mitigates inflammation and injury, leading to improved survival in a murine model of partial-body irradiation (PBI) combined with sepsis. Methods: Mice were exposed to 10 Gy PBI, and at 48 h, they were subjected to cecal ligation and puncture (CLP), a well-established model of sepsis. C23 (8 mg/kg body weight [BW]) or vehicle (saline) was administered subcutaneously at 24 h and 48 h after PBI. Blood and intestinal tissue samples were collected 20 h after CLP (i.e., 68 h post-PBI) for various analyses. In another set of mice after PBI–sepsis, intestinal permeability was also assessed. In an additional cohort of mice subjected to the same experimental procedure, 10-day survival was monitored. Results: Our findings demonstrate that administration of C23 attenuated systemic inflammatory responses, intestinal permeability, intestinal injury, and apoptosis; increased crypt cell proliferation and improved survival after PBI–sepsis. Conclusions: These results reveal a novel protective role of the eCIRP antagonist, C23, in mitigating PBI–sepsis-induced inflammation and injury and represents a promising therapeutic candidate for the treatment of radiation combined injury with sepsis. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)
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19 pages, 707 KB  
Article
Early Identification of a Cytokine-Low Immune Phenotype in Suspected Sepsis Using a Point-of-Care Whole-Blood TNF-α Release Assay
by Erika P. Plata-Menchaca, Berta Cisteró, Adrian Ceccato, Veronica Monforte, Queralt Caus-Capdevila, Aina Areny-Balaguero, Elena Campaña-Duel, Marta Camprubí-Rimblas, Gemma Goma-Fernandez, Carla Guijarro, Patricia Salom, Monica Lopez, Juan Tajan, Tiago Teles De Castro, Vanessa Roman, Joan Vieyra, Judit Cubedo, Eduard Guerrero, Emili Gené, Antonio Artigas and Enrique Hernández-Jiménezadd Show full author list remove Hide full author list
Med. Sci. 2026, 14(4), 465; https://doi.org/10.3390/medsci14040465 - 8 Aug 2026
Viewed by 511
Abstract
Background/Objectives: Routine biomarkers and clinical scores do not directly assess functional immune responsiveness in suspected sepsis. We evaluated whether the TNF-α Release Assay (TARA), a whole-blood LPS-induced functional assay, is associated with an early cytokine-low immune phenotype in Emergency Department (ED) patients. Methods: [...] Read more.
Background/Objectives: Routine biomarkers and clinical scores do not directly assess functional immune responsiveness in suspected sepsis. We evaluated whether the TNF-α Release Assay (TARA), a whole-blood LPS-induced functional assay, is associated with an early cytokine-low immune phenotype in Emergency Department (ED) patients. Methods: In this prospective single-center cohort, adults with suspected sepsis and NEWS2 ≥ 3 were sampled at presentation, at 4 h and, when available, at 24 h. Immune phenotypes were defined independently of TARA by unsupervised k-means clustering of 12 circulating cytokines at 4 h, and a continuous Low-Response Cytokine Score (LRCS) was derived, with higher values indicating lower global cytokine concentrations. Results: Among 152 patients, three phenotypes were identified: C1 cytokine-low (n = 56), C2 inflammatory/intermediate (n = 63), and C3 IFN-γ/MCP-3/IL-17A-high (n = 33). Indicative TARA low-response status was independently associated with a higher LRCS after adjustment for clinical covariates and procalcitonin (PCT), both at presentation (β = 0.33; 95% CI, 0.14–0.53; p = 0.001) and at 4 h (β = 0.38; 95% CI, 0.19–0.57; p < 0.001). Indicative TARA low-response results at 4 h were most frequent in C1 and least frequent in C3 (75% vs. 45%). Exploratory clinical comparisons showed lower recorded early escalation in C1, whereas Sepsis-3 final diagnosis and in-hospital mortality were similar across phenotypes. Conclusions: A TARA low-response status was independently associated with an early circulating cytokine-low phenotype defined without reference to TARA or outcomes, providing information complementary to routine biomarkers and clinical severity scores. These exploratory findings support TARA as a complementary functional immune readout but require external validation and clinical-impact evaluation. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)
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18 pages, 971 KB  
Article
Vasopressor Dosing Trajectories in Septic Shock According to Initial Antimicrobial Susceptibility and Infection Source Concordance: A Retrospective Observational Study
by Yurina Yamaya, Tsukasa Kuwana, Kosaku Kinoshita, Ken Takahashi, Hayato Nakabayashi and Toru Imai
Med. Sci. 2026, 14(3), 394; https://doi.org/10.3390/medsci14030394 - 15 Jul 2026
Viewed by 658
Abstract
Background/Objectives: Septic shock carries high mortality. Although guidelines recommend early empiric antibiotics, early identification of the infection source and selection of appropriate initial antibiotic therapy remain challenging. This study examined whether vasopressor trajectories, quantified as norepinephrine equivalent (NEE), differed according to initial [...] Read more.
Background/Objectives: Septic shock carries high mortality. Although guidelines recommend early empiric antibiotics, early identification of the infection source and selection of appropriate initial antibiotic therapy remain challenging. This study examined whether vasopressor trajectories, quantified as norepinephrine equivalent (NEE), differed according to initial antimicrobial susceptibility and concordance between presumed and final infection sources. Methods: This single-center retrospective observational study included adults with Sepsis-3 septic shock admitted to the intensive care unit between 2017 and 2023. Patients were classified into the appropriate-management group when the initial antibiotic therapy covered the subsequently identified causative pathogen and the initially presumed infection source was concordant with the final infection source; all others were classified into the inappropriate-management group. Primary outcomes were Max NEE duration and the times from Max NEE to 75%, 50%, 25%, and discontinuation of NEE. Results: Among 132 patients analyzed, 101 were classified into the appropriate-management group and 31 into the inappropriate-management group. Max NEE duration was shorter in the appropriate-management group (median (IQR), 4 (2–7) h vs. 6 (3–20) h; p = 0.0100) and remained shorter after excluding deaths during the Max NEE period (n = 119; 6 (2–11) h vs. 11 (5–14) h; p = 0.0314). Time to NEE reduction from Max NEE was shorter in the appropriate-management group, with significant differences at 75% (7 (4–13) h vs. 13 (9–23) h; p = 0.0066) and 25% (19 (13–29) h vs. 31 (16–46) h; p = 0.0247). Conclusions: Prolonged Max NEE duration and delayed NEE reduction were associated with inadequate coverage by initial antibiotic therapy or discordant infection source identification in this selected cohort. Vasopressor trajectories may help prompt reassessment of antibiotic therapy and infection source evaluation. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)
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Review

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26 pages, 2810 KB  
Review
High-Dose Intravenous Vitamin C in Critical Illness: A Translational Exposure–Response Framework for Biomarker-Guided Precision Therapy
by Dejana Bajić, Ljiljana Andrijević, Nemanja Todorović, Mladena Lalić-Popović, Bojan Zarić, Stefan Dimić, Jelena Stojčević Maletić, Dajana Lendak, Boris Milijašević and Nataša Milošević
Med. Sci. 2026, 14(3), 400; https://doi.org/10.3390/medsci14030400 - 17 Jul 2026
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Abstract
High-dose intravenous vitamin C (HDIVC) has been investigated as a potential adjunctive therapy in critical illness, including sepsis, acute respiratory distress syndrome (ARDS), and COVID-19. Despite a strong mechanistic rationale, clinical trials have yielded inconsistent results. From a clinical pharmacology perspective, this variability [...] Read more.
High-dose intravenous vitamin C (HDIVC) has been investigated as a potential adjunctive therapy in critical illness, including sepsis, acute respiratory distress syndrome (ARDS), and COVID-19. Despite a strong mechanistic rationale, clinical trials have yielded inconsistent results. From a clinical pharmacology perspective, this variability may reflect, at least in part, differences in pharmacokinetic exposure, timing of administration, and patient selection rather than a lack of biological activity. Intravenous administration enables plasma concentrations in the millimolar range (≈1–5 mM), far exceeding those achievable with oral dosing (<100 µM), thereby reaching thresholds required for pharmacodynamic effects on oxidative stress, immune signaling, and endothelial function. This exposure-dependent transition distinguishes vitamin C as a pharmacological agent rather than a nutritional supplement in critically ill populations. Therapeutic response may be influenced by timing relative to disease progression, with earlier administration representing a biologically plausible strategy that warrants prospective evaluation rather than a clinically established therapeutic window. Interindividual variability in transporter function, redox status, and genetic background may further contribute to heterogeneous responses. Biomarkers such as interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, and markers of endothelial injury provide a framework for patient stratification and monitoring of pharmacodynamic effects. Integrated with pharmacokinetic principles, these markers support a shift toward biomarker-guided, precision-based therapeutic strategies. This review synthesizes current clinical and mechanistic evidence through an exposure–response conceptual framework, framing HDIVC as a context-dependent pharmacological intervention and advancing a shift toward biomarker-guided, precision-based therapeutic strategies in critical illness. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)
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12 pages, 260 KB  
Review
Role of Thromboelastometry in Sepsis-Induced Coagulopathy: A Narrative Review
by Andrzej Lubiewski and Mariusz Siemiński
Med. Sci. 2026, 14(3), 385; https://doi.org/10.3390/medsci14030385 - 9 Jul 2026
Viewed by 1064
Abstract
Sepsis-induced coagulopathy (SIC) represents an early, predominantly prothrombotic disturbance that is difficult to detect using conventional coagulation tests. This review aims to evaluate whether rotational thromboelastometry (ROTEM) provides added value in the diagnosis and phenotyping of SIC compared with standard laboratory parameters. We [...] Read more.
Sepsis-induced coagulopathy (SIC) represents an early, predominantly prothrombotic disturbance that is difficult to detect using conventional coagulation tests. This review aims to evaluate whether rotational thromboelastometry (ROTEM) provides added value in the diagnosis and phenotyping of SIC compared with standard laboratory parameters. We summarize current evidence on SIC pathophysiology and its relationship to disseminated intravascular coagulation (DIC), with particular focus on mechanisms driving hypercoagulability and fibrinolytic shutdown. The limitations of routine tests, platelet count, PT/INR, fibrinogen, and fibrin-related markers are examined, especially their inability to capture early dynamic changes in coagulation. We then outline the principles of ROTEM and review clinical studies assessing its application in sepsis. Available data consistently demonstrate increased clot firmness, frequently driven by elevated fibrinogen, along with impaired fibrinolysis. These patterns often precede overt SIC or DIC and are associated with worse clinical outcomes, including organ dysfunction and mortality. Finally, we discuss the implications of these findings for clinical management. While routine anticoagulation in unselected septic patients remains unsupported, integrating SIC criteria with ROTEM profiles may improve risk stratification and help identify prothrombotic phenotypes that could benefit from targeted therapies. Overall, ROTEM appears to be a valuable adjunct to conventional testing, with potential to refine diagnostic accuracy and guide future interventional strategies in septic coagulopathy. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)

Other

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22 pages, 1296 KB  
Systematic Review
Hyperoncotic Albumin (20%) Versus Crystalloids for Mortality in Adults with Sepsis and Septic Shock: An Updated Systematic Review and Meta-Analysis
by Christian J. Wiedermann, Gianni Turcato, Arian Zaboli and Michael Joannidis
Med. Sci. 2026, 14(5), 550; https://doi.org/10.3390/medsci14050550 - 7 Sep 2026
Viewed by 799
Abstract
Background/Objective: Hyperoncotic albumin (20%) has been proposed for sepsis; however, the randomized evidence is inconclusive, and the 2026 Surviving Sepsis Campaign guidelines now suggest crystalloids alone while permitting albumin on a case-by-case basis. We updated the evidence, restricting the intervention to hyperoncotic albumin [...] Read more.
Background/Objective: Hyperoncotic albumin (20%) has been proposed for sepsis; however, the randomized evidence is inconclusive, and the 2026 Surviving Sepsis Campaign guidelines now suggest crystalloids alone while permitting albumin on a case-by-case basis. We updated the evidence, restricting the intervention to hyperoncotic albumin (≥20%) and the comparator exclusively to crystalloids, and examined whether the benefit was confined to septic shock. Methods: We searched PubMed, EMBASE, and Cochrane CENTRAL (March 2024–March 2026), supplementing a previously published meta-analysis. Randomized trials of hyperoncotic albumin versus crystalloids in adults with sepsis or septic shock reporting all-cause mortality were included. The primary outcome was mortality at the longest follow-up, pooled as risk ratios (RRs) using random-effects models. Given negligible heterogeneity, the estimate was reported under standard, Hartung–Knapp–Sidik–Jonkman (HKSJ), truncated-HKSJ, and fixed-effects methods, with a Bayesian sensitivity analysis. A pre-specified subgroup contrasted septic shock with sepsis without shock. This review was registered in PROSPERO (CRD420261334243). Results: Eight RCTs (n = 3707) provided the data; all administered 20% albumin. Overall, albumin was not robustly associated with reduced mortality (RR 0.94; I2 = 0%), significant only under the pre-registered HKSJ correction (0.91–0.98) but null under the standard, truncated-HKSJ, and fixed-effects models (0.87–1.03, p = 0.17), identifying this as a low-heterogeneity artifact. In septic shock (k = 6), the effect was larger and consistent (RR 0.90, 0.82–0.99, p = 0.03), with no benefit in sepsis without shock (RR 1.10; interaction p = 0.08). The certainty was low (GRADE). Conclusions: In adults with sepsis, hyperoncotic albumin was not associated with a statistically significant reduction in all-cause mortality, and the certainty of evidence was low (GRADE). This is consistent with the 2026 Surviving Sepsis Campaign guidelines, which permit case-by-case use of albumin in this setting but do not recommend its routine use. Adequately powered randomized trials are required. Full article
(This article belongs to the Special Issue Sepsis Management and Therapeutic Strategies: From Early Recognition to Advanced Interventions)
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