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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
Bone, R. C., BALK, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., Schein, R. M. H., & Sibbald, W. J. (1992) · CHEST Journal · doi:10.1378/chest.101.6.1644 · Cited by 13,317
Early goal-directed therapy in the treatment of severe sepsis and septic shock
Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., & Tomlanovich, M. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010307 · Cited by 10,743
Angus, D. C., Linde-Zwirble, W. T., Lidicker, J., Clermont, G., Carcillo, J., & Pinsky, M. R. (2001) · Critical Care Medicine · doi:10.1097/00003246-200107000-00002 · Cited by 8,503
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631
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
Dinarello, C. A. (1984) · Clinical Infectious Diseases · doi:10.1093/clinids/6.1.51 · Cited by 1,647
Ziegler, E. J., Fisher, C. J., Sprung, C. L., Straube, R., SADOFF, J. C., Foulke, G. E., Wortel, C. H., Fink, M. P., Dellinger, R. P., Teng, N. N. H., et al. (1991) · New England Journal of Medicine · doi:10.1056/nejm199102143240701 · Cited by 1,618
A network-based analysis of systemic inflammation in humans
Program, I. A. H. R. T. I. L. S. C. R., Calvano, S. E., Xiao, W., Richards, D. R., Felciano, R. M., Baker, H. V., Cho, R. J., Chen, R. O., Brownstein, B. H., Cobb, J. P., et al. (2005) · Nature · doi:10.1038/nature03985 · Cited by 1,429
Drotrecogin Alfa (Activated) in Adults with Septic Shock
Ranieri, V. M., Thompson, B., Barie, P. S., Dhainaut, J.-F., Douglas, I. S., Finfer, S. R., Gårdlund, B., Marshall, J. C., Rhodes, A., Artigas, A., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1202290 · Cited by 1,306
Self-citationA genomic storm in critically injured humans
Xiao, W., Mindrinos, M. N., Seok, J., Cuschieri, J., Cuenca, A. G., Gao, H., Hayden, D. L., Hennessy, L. V., Moore, E. E., Minei, J. P., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20111354 · Cited by 1,246
Treatment of Gram-Negative Bacteremia and Shock with Human Antiserum to a MutantEscherichia coli
Ziegler, E. J., McCutchan, J. A., Fierer, J., Glauser, M. P., SADOFF, J. C., Douglas, H., & Braude, A. I. (1982) · New England Journal of Medicine · doi:10.1056/nejm198211113072001 · Cited by 1,044
Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome
Casey, L. C., Balk, R. A., & Bone, R. C. (1993) · Annals of Internal Medicine · doi:10.7326/0003-4819-119-8-199310150-00001 · Cited by 1,039
Levy, M. M., Dellinger, R. P., Townsend, S. R., Linde‐Zwirble, W. T., Marshall, J. C., Bion, J., Schorr, C., Artigas, A., Ramsay, G., Beale, R. J., et al. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181cb0cdc · Cited by 965
Self-citationLópez, A., Lorente, J. A., Steingrub, J. S., Bakker, J., McLuckie, A., Willatts, S. M., Brockway, M., Anzueto, A., Holzapfel, L., Breen, D. P., et al. (2004) · Critical Care Medicine · doi:10.1097/01.ccm.0000105581.01815.c6 · Cited by 917
Confirmatory interleukin-1 receptor antagonist trial in severe sepsis
Opal, S. M., Fisher, C. J., Dhainaut, J.-F., Vincent, J., Brase, R., Lowry, S. F., SADOFF, J. C., Slotman, G. J., Levy, H. A., BALK, R. A., et al. (1997) · Critical Care Medicine · doi:10.1097/00003246-199707000-00010 · Cited by 882
Genetic and Environmental Influences on Premature Death in Adult Adoptees
Sørensen, T. I. A., Nielsen, G. G., Andersen, P. K., & Teasdale, T. W. (1988) · New England Journal of Medicine · doi:10.1056/nejm198803243181202 · Cited by 826
Opal, S. M., Laterre, P.-F., Francois, B., LaRosa, S. P., Angus, D. C., Mira, J.-P., Wittebole, X., Dugernier, T., Perrotin, D., Tidswell, M., et al. (2013) · JAMA · doi:10.1001/jama.2013.2194 · Cited by 812
Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group.
Bone, R. C., Fisher, C. J., Clemmer, T. P., Gj, S., METZ, C. A., & BALK, R. A. (1989) · PubMed · Cited by 689
Abraham, E., Anzueto, A., Gutierrez, G., Tessler, S., Pedro, G. S., Wunderink, R., Nogare, A. D. D., Nasraway, S., Berman, S., Cooney, R., et al. (1998) · The Lancet · doi:10.1016/s0140-6736(05)60602-2 · Cited by 681
Abraham, E. H., Anzueto, A., Gutiérrez, G., Tessler, S., Pedro, G. S. S., Wunderink, R. G., Nogare, A. R. D., Nasraway, S. A., Berman, S., Cooney, R. N., et al. (1998) · PubMed · Cited by 622
HER2 and Response to Paclitaxel in Node-Positive Breast Cancer
Hayes, D. F., Thor, A. D., Dressler, L. G., Weaver, D. L., Edgerton, S. M., Cowan, D., Broadwater, G., Goldstein, L. J., Martino, S., Ingle, J. N., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa071167 · Cited by 603
Steroids in the Treatment of Clinical Septic Shock
SCHUMER, W. (1976) · Annals of Surgery · doi:10.1097/00000658-197609000-00011 · Cited by 547
Bone, R. C., Fisher, C. J., Clemmer, T. P., Slotman, G. J., METZ, C. A., & BALK, R. A. (1989) · Critical Care Medicine · doi:10.1097/00003246-198905000-00002 · Cited by 535
Treatment of Septic Shock with Human Monoclonal Antibody HA-1A
McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M., Smith, C. R., & and CHESS Trial Study Group. (1994) · Annals of Internal Medicine · doi:10.7326/0003-4819-121-1-199407010-00001 · Cited by 492
Levin, M., Quint, P. A., Goldstein, B., Barton, P., Bradley, J. S., Shemie, S., Yeh, T. S., Kim, S. S., Cafaro, D. P., Scannon, P. J., et al. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02712-4 · Cited by 408
Panacek, E. A., Marshall, J. C., Albertson, T. E., Johnson, D. H., Johnson, S. B., MacArthur, R. D., Miller, M. J., Barchuk, W., Fischkoff, S. A., Kaul, M., et al. (2004) · Critical Care Medicine · doi:10.1097/01.ccm.0000145229.59014.6c · Cited by 393
Self-citationReinhart, K., Wiegand-Löhnert, C., Grimminger, F., Kaul, M., Withington, S., Treacher, D., Eckart, J., Willatts, S. M., Bouza, C., Krausch, D., et al. (1996) · Critical Care Medicine · doi:10.1097/00003246-199605000-00003 · Cited by 358
Marshall, J. C., & Reinhart, K. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181a02afc · Cited by 316
Self-citationLong-term Survival and Function After Suspected Gram-negative Sepsis
Perl, T. M. (1995) · JAMA · doi:10.1001/jama.1995.03530040066043 · Cited by 305
Winthrop, K. L. (2006) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0336 · Cited by 277
Aaltonen, K., Virkki, L. M., Malmivaara, A. O. V., Konttinen, Y. T., Nordström, D., & Blom, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030275 · Cited by 273
Such stuff as dreams are made on: mediator-directed therapy in sepsis
Marshall, J. C. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1084 · Cited by 269
Self-citationThe Primary Role of Lymphoreticnlar Cells in the Mediation of Host Responses to Bacterial Endotoxim
Michalek, S. M., Moore, R. N., McGhee, J. R., Rosenstreich, D. L., & Mergenhagen, S. E. (1980) · The Journal of Infectious Diseases · doi:10.1093/infdis/141.1.55 · Cited by 208
Microbial Infection and the Septic Response in Critical Surgical Illness
Marshall, J. C. (1990) · Archives of Surgery · doi:10.1001/archsurg.1990.01410130019002 · Cited by 157
Self-citationBaumgartner, J. D., Heumann, D., Gérain, J., Weinbreck, P., Grau, G. E., & Glauser, M. P. (1990) · The Journal of Experimental Medicine · doi:10.1084/jem.171.3.889 · Cited by 150
The Framingham Study : ITS 50-Year Legacy and Future Promise
Kannel, W. B. (2000) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat1994.6.60 · Cited by 147
STUDIES ON THE PATHOGENESIS OF FEVER
Atkins, E., & Wood, W. B. (1955) · The Journal of Experimental Medicine · doi:10.1084/jem.102.5.499 · Cited by 146
Sepsis: rethinking the approach to clinical research
Marshall, J. C. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0607380 · Cited by 141
Self-citationEarly events in the recognition of danger signals after tissue injury
Kaczorowski, D. J., Mollen, K. P., Edmonds, R. D., & Billiar, T. R. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0607374 · Cited by 121
NEUTRALIZATION OF TUMOR NECROSIS FACTOR IN PRECLINICAL MODELS OF SEPSIS
Lorente, J. A., & Marshall, J. C. (2005) · Shock · doi:10.1097/01.shk.0000191343.21228.78 · Cited by 112
Self-citationEsmon, C. T. (2003) · Journal of Endotoxin Research · doi:10.1179/096805103125001603 · Cited by 94
The Ancient Riddle of Formula (Sepsis)
Majno, G. (1991) · The Journal of Infectious Diseases · doi:10.1093/infdis/163.5.937 · Cited by 92
Lipopolysaccharide: An Endotoxin or an Exogenous Hormone?
Marshall, J. C. (2005) · Clinical Infectious Diseases · doi:10.1086/432000 · Cited by 89
Self-citationSeptic Shock — Evaluating Another Failed Treatment
Wenzel, R. P., & Edmond, M. B. (2012) · New England Journal of Medicine · doi:10.1056/nejme1203412 · Cited by 78
Rivers, E. P., Jaehne, A. K., Nguyen, H. B., Papamatheakis, D. G., Singer, D., Yang, J. J., Brown, S., & Klausner, H. (2013) · Shock · doi:10.1097/shk.0b013e31827dafa7 · Cited by 66
Another negative clinical trial of a new agent for the treatment of sepsis
Fink, M. P. (1995) · Critical Care Medicine · doi:10.1097/00003246-199506000-00001 · Cited by 56
The PIRO (predisposition, insult, response, organ dysfunction) model
Marshall, J. C. (2013) · Virulence · doi:10.4161/viru.26908 · Cited by 55
Self-citationInFACT: a global critical care research response to H1N1
The InFACT Global H N Collaboration‡ (2009) · The Lancet · doi:10.1016/s0140-6736(09)61792-x · Cited by 50
Intensive care triage—The hardest rationing decision of them all*
Levin, P. D., & Sprung, C. L. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000208355.77757.9c · Cited by 31
Biotechnology and Clinical Trials
Siegel, J. P. (2002) · The Journal of Infectious Diseases · doi:10.1086/338061 · Cited by 5
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
The immunopathology of sepsis and potential therapeutic targets
van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P., & Netea, M. G. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.36 · Cited by 1,957
Hotchkiss, R. S., Moldawer, L. L., Opal, S. M., Reinhart, K., Turnbull, I. R., & Vincent, J. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.45 · Cited by 1,795
Sepsis: pathophysiology and clinical management
Gotts, J. E., & Matthay, M. A. (2016) · BMJ · doi:10.1136/bmj.i1585 · Cited by 1,308
Practitioner’s guide to latent class analysis: Methodological considerations and common pitfalls
Sinha, P., Calfee, C. S., & Delucchi, K. L. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000004710 · Cited by 1,204
van der Poll, T., Shankar‐Hari, M., & Wiersinga, W. J. (2021) · Immunity · doi:10.1016/j.immuni.2021.10.012 · Cited by 1,094
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
About these checks
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 ›
Are you an author, or do you see a problem with this page? Request a review
