Why have clinical trials in sepsis failed?

Marshall, John C.

doi:10.1016/j.molmed.2014.01.007

Cited by 810Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysVitamin C and Antioxidants Research

Why have clinical trials in sepsis failed?

Marshall, John C.·2014·Trends in Molecular Medicine

DOI 10.1016/j.molmed.2014.01.007

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Abstract

The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit.

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The underlying molecular mechanisms behind pathological capillary leakage remain incompletely understood, hindering the development of targeted therapies aimed at vascular stabilization.
“The underlying molecular mechanisms behind pathological capillary leakage remain incompletely understood, hindering the development of targeted therapies aimed at vascular stabilization (3).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [3]
Increased capillary leakage leading to hypovolemic shock and multiorgan failure is a key event in the pathobiology of several difficult-to-treat conditions, such as sepsis.
“Increased capillary leakage leading to hypovolemic shock and multiorgan failure is a key event in the pathobiology of several difficult-to-treat conditions, such as sepsis (2, 3, 6).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [3]

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Background
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Authors: Marshall, J. C.
Affiliations: St. Michael's Hospital (CA)
Corresponding author: Marshall, John C.
ORCID: Marshall, John C.
Venue: Trends in Molecular Medicine
Publisher: Elsevier BV
Published: 2014-04
Volume: 20
Issue: 4
Pages: 195-203
ISSN: 1471-4914 (ISSN-L)
DOI: 10.1016/j.molmed.2014.01.007
OpenAlex: W1991209345
Cited by: 805
References: 56
Citations by year: 2026: 77 · 2025: 75 · 2024: 69 · 2023: 75 · 2022: 96 · 2021: 66 · 2020: 72 · 2019: 69 · 2018: 59 · 2017: 62 · 2016: 45 · 2015: 28 · 2014: 12
FWCI: 6.58
Type: journal article
Language: en
Open access: closed
Locations: Trends in Molecular Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
Keywords: sepsis, clinical trial failure, systemic inflammatory response, sepsis treatment, translational research, patient stratification, sepsis epidemiology, inflammatory markers
MeSH terms: Animals, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Immunity, Innate, Immunologic Factors, Treatment Outcome, Sepsis

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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Why have clinical trials in sepsis failed?

Abstract

Integrity signals

Claims the paper makes

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