The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index.
Why have clinical trials in sepsis failed?
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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Over the last 40 years, more than 100 clinical trials of would‐be sepsis drugs aimed at modulating host immune responses to infection have failed.”
From On race, human variation, and who gets and dies of sepsis (2022) · cites this paper as Marshall, 2014
Citations
Cites
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Early goal-directed therapy in the treatment of severe sepsis and septic shock
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Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
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Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
Bernard, G. R., Vincent, J., Laterre, P., LaRosa, S. P., Dhainaut, J.-F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G. E., Helterbrand, J. D., Ely, E. W., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200103083441001 · Cited by 6,124
2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference
Levy, M. M., Fink, M. P., Marshall, J. C., Abraham, E. H., Angus, D. C., Cook, D., Cohen, J., Opal, S. M., Vincent, J., & Ramsay, G. (2003) · Critical Care Medicine · doi:10.1097/01.ccm.0000050454.01978.3b · Cited by 5,976
Self-citationIntensive versus Conventional Glucose Control in Critically Ill Patients
(2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810625 · Cited by 5,119
Genomic responses in mouse models poorly mimic human inflammatory diseases
Seok, J., Warren, H. S., Cuenca, A. G., Mindrinos, M. N., Baker, H. V., Xu, W., Richards, D. R., McDonald-Smith, G. P., Gao, H., Hennessy, L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222878110 · Cited by 3,005
Functional Disability 5 Years after Acute Respiratory Distress Syndrome
Herridge, M. S., Tansey, C. M., Matte, A. L., TOMLINSON, G. A., Diaz-Granados, N., Cooper, A., Guest, C. B., Mazer, C. D., Mehta, S., Stewart, T. E., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1011802 · Cited by 2,892
Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia
Tracey, K. J., Fong, Y., Hesse, D. G., Manogue, K. R., Lee, A. T., Kuo, G. C., Lowry, S. F., & Cerami, A. (1987) · Nature · doi:10.1038/330662a0 · Cited by 2,448
Flagged first, then by citations
1 of the 56 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Centers for Disease Control and Prevention, 1999, Achievements in public health, 1900–1999, MMWR, 48, 621
Cited by
Sorted by citations
Items 801–810 of 810
Interleukin‐39 is a Prognostic Biomarker and Therapy Target for Sepsis
Zhang, F.-Z., Liu, H., Yue, Y., Gao, J., Zhang, J., Zhang, W., Zhang, Y., Lü, W., Jin, S., & Zhang, P. (2026) · Advanced Science · doi:10.1002/advs.77663
Abbas, B., Abbas, A., Khan, I., & Nazeer, S. (2026) · Clinical Immunology · doi:10.1016/j.clim.2026.110782
Wang, C., Xi, C., Zhang, Y., Ma, R.-F., Shi, M.-M., Gao, Y., Liu, L.-P., Ning, C.-Y., & Chen, A.-B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1973456
Beloussov, V., Strochkov, V. M., Sandybayev, N. T., Lavrinenko, A. V., Aitpenov, T., & Solomadin, M. (2026) · Diagnostics · doi:10.3390/diagnostics16203410
Antcliffe, D. B., Uhle, F., Marshall, D. C., Green, A. D., Gordon, A. C., & Forni, L. G. (2026) · Critical Care Explorations · doi:10.1097/cce.0000000000001496
Yan, X., Li, M., Yan, C., Dang, Y., Lv, Y., 李同琴, Zhang, J., Wu, Y., & Ma, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1935801
Coupland, L. A., Self, M., Suryana, E., Law, R., Crispin, P., Keragala, C. B., Frost, S., Rabbolini, D. J., Moore, P., Medcalf, R. L., et al. (2026) · medRxiv · doi:10.64898/2026.10.24.26366402
White, C., Martinelli, R., Parthasarathy, U., Thakur, G., Hogan, J., & Kuang, Y. (2022) · Harvard Dataverse · doi:10.7910/dvn/1gtqai
Sepsis: Epidemiology, Pathophysiology, and Management
Pan, G., Deng, Y., Ma, L., Li, Y., Qian, Y., Ma, Y., Rao, H., Zhu, Y., & Yan, P. (2026) · MedComm · doi:10.1002/mco2.71079
Metadata
- 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)
- 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 › Critical Care and Intensive Care Medicine › 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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