Open research questions in Sepsis Diagnosis and Treatment

What the literature leaves open

• The class imbalance in the collected data sample, with more negative cases than positive cases. The risk of false positives due to low precision. The need for external validation of the model in different healthcare systems and regions.

  Analysis and implications of validation results for a clinical data-based early warning model for geriatric sepsis · 2026 · DOI

• true external validation is needed, - evaluating the model's applicability in external hospitals, different regions, and healthcare systems with significant differences in clinical practices

  Analysis and implications of validation results for a clinical data-based early warning model for geriatric sepsis · 2026 · DOI

• The gap in current research is the lack of understanding of how to effectively incorporate ancillary data into CPM development. The study identifies the need to account for heterogeneity between the target and ancillary data sets. The gap also includes the need for methods to adjust for distributional changes between the target and ancillary data sets.

  Comparison of Methods for Incorporating Related Data When Developing Clinical Prediction Models: A Simulation Study · 2026 · DOI

• The pathophysiological mechanism of SALI remains unclear. The prognosis of patients with SALI remains unsatisfactory. Identifying prognostic biomarkers for patients with SALI is necessary.

  Association between the prognostic nutritional index and 28-day mortality in patients with sepsis-associated liver injury: a retrospective cohort study · 2026 · DOI

• Further studies are needed to explore the role of the PNI in the context of SALI, - Investigation of the pathophysiological mechanism of SALI is necessary, - Identification of prognostic biomarkers for patients with SALI is required

  Association between the prognostic nutritional index and 28-day mortality in patients with sepsis-associated liver injury: a retrospective cohort study · 2026 · DOI

• Existing clinical scoring systems have limited predictive performance. There is a need for an interpretable machine learning model to predict in-hospital mortality in sepsis patients. The current study aims to address this gap.

  Development of an interpretable machine learning model for predicting in-hospital mortality in ICU patients with sepsis: a retrospective cohort study · 2026 · DOI

• Missingness in key clinical and laboratory variables. Covariate imbalance across phenotype groups. The need for a paired classification of chloride and bicarbonate to characterize risk.

  Association of early chloride-bicarbonate joint phenotypes with in-hospital mortality among intensive care unit patients with sepsis: a dual-database study · 2026 · DOI

• further study of the boundaries of these findings, - investigation of the incremental predictive value of chloride-bicarbonate phenotypes, - analysis of the acid-base effects of intravenous fluids

  Association of early chloride-bicarbonate joint phenotypes with in-hospital mortality among intensive care unit patients with sepsis: a dual-database study · 2026 · DOI

• The study had substantial inter-study heterogeneity (I 2 = 86.2%, P < 0.001), - The study excluded studies related to other infectious diseases such as hepatitis due to lack of extractable HRs and 95% CIs for survival outcomes, - The study relied on a simplified PNI formula which may not capture the full complexity of nutritional status

  Prognostic value of the prognostic nutritional index in sepsis, pneumonia, and tuberculosis: a systematic review and meta-analysis · 2026 · DOI

• Further studies are needed to explore the prognostic value of PNI in other infectious diseases, - Research should investigate the underlying pathophysiological mechanisms of PNI in infectious diseases, - Studies should examine the optimal PNI cutoff value for predicting mortality and unfavorable outcomes

  Prognostic value of the prognostic nutritional index in sepsis, pneumonia, and tuberculosis: a systematic review and meta-analysis · 2026 · DOI

• Further studies are needed to confirm the findings and explore the potential benefits of carvedilol in sepsis. Subgroup analysis further revealed that the Charlson Comorbidity Index (CCI) acted as an effect modifier of the efficacy of carvedilol, which could be explored in future research.

  Association of carvedilol with mortality in critically ill patients with sepsis: a retrospective propensity score-matched cohort study · 2026 · DOI

• The conventional management of sepsis does not adequately address the dysregulated host immune response. There is a need for immune-based therapeutic strategies to improve sepsis outcomes.

  Association of carvedilol with mortality in critically ill patients with sepsis: a retrospective propensity score-matched cohort study · 2026 · DOI

• Translating biological discoveries into effective clinical interventions. The challenge of integrating longitudinal publication trends with granular contemporary insights. The need for substantial investment in electronic health record infrastructure and data science personnel to deploy algorithmic monitoring for severe complications.

  Thirty-five years of evolving inflammatory paradigms in sepsis (1991–2025): a comprehensive mapping of immune dysregulation research, anti-inflammatory targets, and translational barriers · 2026 · DOI

• Investigating emerging trends at the intersection of data science, molecular immunology, and targeted pharmacology - Exploring underexplored mechanisms or pathways - Developing mechanism-driven precision approaches

  Thirty-five years of evolving inflammatory paradigms in sepsis (1991–2025): a comprehensive mapping of immune dysregulation research, anti-inflammatory targets, and translational barriers · 2026 · DOI

• The complexity of sepsis syndrome and its high mortality rate. The need for reliable and easily implementable biomarkers to improve prognosis in urosepsis patients. The challenge of individualized, source-based precision medicine in sepsis management.

  The relationship between improved elderly nutritional risk index and short-term all-cause mortality in patients with urinary sepsis: a retrospective cohort study · 2026 · DOI

• The study was retrospective, - The sample size was limited to 1,875 patients, - The study only included patients with urosepsis, - The external validation cohort was small (281 patients)

  The relationship between improved elderly nutritional risk index and short-term all-cause mortality in patients with urinary sepsis: a retrospective cohort study · 2026 · DOI

• Heterogeneity in patient phenotypes and treatment responses. Difficulty in establishing a universally superior vasopressor strategy. Need for repeated physiological interpretation and dynamic reassessment.

  Septic shock in the era of precision medicine: rethinking fluids, vasopressors, and immunomodulation · 2026 · DOI

• current practice is limited by managing septic shock as a single clinical entity - biologically plausible therapies frequently fail when tested in unselected populations - most immunomodulatory strategies remain investigational outside established corticosteroid use in selected vasopressor-dependent shock

  Septic shock in the era of precision medicine: rethinking fluids, vasopressors, and immunomodulation · 2026 · DOI

• The study faces the challenge of capturing complex interactions between clinical variables. The study must address the issue of blood pressure variability in critically ill patients with hypertension. The study needs to develop predictive models that can accurately distinguish between patients who survived and those who did not after ICU admission.

  Predicting mortality in critically ill patients with hypertension using machine learning and deep learning models · 2025 · DOI

• Traditional prognostic tools often fall short in capturing complex interactions between clinical variables. There is a need for more sophisticated and accurate predictive models to guide clinical decision-making.

  Predicting mortality in critically ill patients with hypertension using machine learning and deep learning models · 2025 · DOI

• Strengths and limitations of this studyO_LIMANTRA is a randomized trial comparing angiotensin-II against an active standard-of-care norepinephrine strategy rather than placebo, enrolling patients earlier in septic shock than prior trials restricted to catecholamine-resistant shock.

  Mechanistic Assessment of Norepinephrine Therapy versus Angiotensin-II in Septic Shock (MANTRA): Study Protocol for a multicenter randomized trial · 2026 · DOI

• The downstream effect on hospital benchmarking is not yet quantified and should not be presumed negligible.

  Do established comorbidity scores predict in-hospital mortality equally well in women and men? A nationwide validation in 166.7 million German inpatient cases, 2010-2024 · 2026 · DOI

• ICU mortality in Ethiopia is higher than in developed nations, but data from private-hospital ICUs are lacking.

  Prevalence of Mortality and Associated Factors in the Adult Intensive Care Unit of a Private Hospital in Addis Ababa, Ethiopia · 2026 · DOI

• BACKGROUND: Although the lactate dehydrogenase-to-serum albumin ratio (LAR) has been associated with adverse outcomes in adult critical care, its prognostic value in pediatric intensive care unit (PICU) patients remains unclear.

  Association between lactate dehydrogenase to serum albumin ratio and all-cause mortality among critically ill pediatrics: a retrospective cohort study · 2026 · DOI

• The systemic immune-inflammation (SII) index, integrating neutrophils, platelets, and lymphocytes, has shown prognostic value in various diseases but remains understudied in sepsis.

  Systemic immune-inflammation (SII) index as a novel prognostic biomarker in critically ill patients with sepsis: analysis of the MIMIC-IV cohort and predictive modeling based on machine learning · 2026 · DOI

Most-cited papers in Sepsis Diagnosis and Treatment

• The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) · JAMA · 2016 · 24,089 citations
• Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock · New England Journal of Medicine · 2001 · 7,908 citations
• Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study · The Lancet · 2020 · 6,763 citations
• The Epidemiology of Sepsis in the United States from 1979 through 2000 · New England Journal of Medicine · 2003 · 4,719 citations
• Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis · New England Journal of Medicine · 2001 · 4,557 citations
• Assessment of Clinical Criteria for Sepsis · JAMA · 2016 · 3,368 citations
• Severe Sepsis and Septic Shock · New England Journal of Medicine · 2013 · 3,191 citations
• The Pathophysiology and Treatment of Sepsis · New England Journal of Medicine · 2003 · 3,124 citations
• Serial Evaluation of the SOFA Score to Predict Outcome in Critically Ill Patients · JAMA · 2001 · 2,239 citations
• Sepsis and septic shock · The Lancet · 2018 · 2,062 citations

Most recent work

• Sepsis · The Lancet · 2026
• Multicenter Prospective Validation of an Updated Proprietary Sepsis Prediction Model · JAMA Network Open · 2026
• An artificial intelligence-powered learning health system to improve sepsis detection and quality of care: a before-and-after study · npj Digital Medicine · 2026
• Progress in sepsis prediction models: from traditional scoring systems to multimodal intelligence and clinical translation · Frontiers in Medicine · 2026
• National Estimates of Pediatric Sepsis in US Hospitals Using Clinical Data · JAMA · 2026
• Development and validation of a nutrition-integrated nomogram for predicting 28-day mortality in sepsis patients · Frontiers in Nutrition · 2026
• Machine Learning Prediction of ICU Mortality and Length of Stay in Atrial Fibrillation: A MIMIC-IV/MIMIC-III Study · Healthcare · 2026
• Evolutionary digital twin framework for optimal aminoglycoside dosing in neonates with suspected sepsis · npj Digital Medicine · 2026
• The relationship between improved elderly nutritional risk index and short-term all-cause mortality in patients with urinary sepsis: a retrospective cohort study · Frontiers in Nutrition · 2026
• Integrating dynamic SOFA changes and age to predict 28-day mortality in ICU patients: a nomogram and machine learning validation study · Frontiers in Medicine · 2026

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