Sepsis: rethinking the approach to clinical research

@article{Marshall2008SepsisRT,
  title={Sepsis: rethinking the approach to clinical research},
  author={John C. Marshall},
  journal={Journal of Leukocyte Biology},
  year={2008},
  volume={83}
}
  • J. Marshall
  • Published 1 March 2008
  • Medicine, Biology
  • Journal of Leukocyte Biology
The clinical syndrome of sepsis encompasses a highly heterogeneous group of clinical disorders, varying with respect to the site, bacteriology, and even presence of infection and with the clinical syndrome evolving in the host. Clinical trials of strategies to modulate the host response that mediates sepsis were first initiated 25 years ago. A continuing record of disappointment has characterized subsequent work, and only a single new therapy has been licensed for clinical use. Yet, these… 
View on Wiley
ncbi.nlm.nih.gov
146 Citations
Highly Influential Citations
8
Background Citations
69
Methods Citations
2
Results Citations
2

146 Citations

Septic shock: desperately seeking treatment.
TLDR
The most recent findings are discussed in relation to the understanding of the underlying mechanisms involved in septic shock, and the attempts made to improve animal experimental models are highlighted.
Why have clinical trials in sepsis failed?
Novel pharmacologic approaches to the management of sepsis: targeting the host inflammatory response.
TLDR
Several novel therapeutic adjuncts for the management of critically ill patients with sepsis are reviewed, largely focus on those therapies that directly target the host inflammatory response, specifically those that result in activation of the transcription factor, nuclear factor (NF)-kappaB.
Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient.
TLDR
Advanced knowledge about the complex regulation of inflammatory mediators and their overlapping involvement in other potentially life-threatening diseases, further evaluation of these approaches in relevant subgroups could help to identify critically ill patients with potential benefit from anti-inflammatory therapies.
Mechanisms and Regulation of the Gene-Expression Response to Sepsis
TLDR
It is hypothesized that an improved mechanistic understanding obtained via basic and translational science will continue to identify novel therapeutic targets and approaches for pediatric sepsis and septic shock, and emerging data from genetic, genomic, and other translation studies in Pediatrics will advance biological understanding of this response.
Towards Clinical Applications of Anti-endotoxin Antibodies; A Re-appraisal of the Disconnect
TLDR
New insights are examined into the complex relationship between endotoxemia and sepsis in an attempt to bridge this disconnect and several new factors to consider include the frequency and types of GN bacteremia and the underlying mortality risk in the various study populations.
New approaches to the study of sepsis
  • P. Ward
  • Biology, Medicine
    EMBO molecular medicine
  • 2012
TLDR
Events developing early in sepsis suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance, which contributes to the harmful effects of sepsi.
The sepsis syndrome and the "one size fits all" construct: the emperor has not clothes!!
TLDR
The present study has demonstrated that an unsupervised clustering technique based on frequently collected demographic, clinical and physiologic data can be used to derive distinct, biologically sound clusters of patients who clinically behave differently from each other.
Sepsis: current dogma and new perspectives.
Sepsis
TLDR
The management of the child with sepsis represents the sine qua non of pediatric critical care medicine and successful management of critically ill children depends upon early recognition, early treatment with antibiotics, and early reversal of shock.
...
...

References

SHOWING 1-10 OF 96 REFERENCES
Such stuff as dreams are made on: mediator-directed therapy in sepsis
  • J. Marshall
  • Biology, Medicine
    Nature Reviews Drug Discovery
  • 2003
TLDR
This review summarizes the approaches that have been evaluated in clinical trials, explores the reasons for the discordance between biological promise and clinical reality, and points to approaches that may lead to greater success in the future.
Clinical trials of immunomodulatory therapies in severe sepsis and septic shock.
TLDR
The positive and negative results of trials in this field are discussed; some of the possible reasons for the negative results are examined, and directions for the future are suggested.
Outcome measures for clinical research in sepsis: A report of the 2nd Cambridge Colloquium of the International Sepsis Forum
TLDR
The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill.
The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study.
TLDR
This prospective epidemiologic study of SIRS and related conditions provides the first evidence of a clinical progression from SirS to sepsis to severe sepsi and septic shock, and stepwise increases in mortality rates in the hierarchy.
New strategies for clinical trials in patients with sepsis and septic shock
TLDR
Important changes in several aspects of trial design may improve the quality of clinical studies in sepsis and maximize the chance of identifying effective therapeutic agents.
Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome
TLDR
Study of lipopolysaccharide and cytokine levels in 97 patients with the sepsis syndrome found a positive correlation between high levels of plasma TNF- and mortality, and implicate T NF- as an important mediator in sepsi.
NEUTRALIZATION OF TUMOR NECROSIS FACTOR IN PRECLINICAL MODELS OF SEPSIS
TLDR
It is concluded that the beneficial effects of T NF in systemic inflammation occur at the cost of impaired antimicrobial defenses, and that a better understanding of the consequences of neutralization of TNFα in vivo could aid in better defining optimal patient populations for therapeutic intervention.
Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy.
TLDR
The evidence for a genetic susceptibility to development of sepsis and death from sepsic shock is summarized, the design of clinical genetics studies relevant to the study of complex disorders are discussed, the candidate genes likely to be involved in the pathogenesis of sePSis are considered, and the potential for targeted therapy of septic shock based on genetic variability is discussed.
Microbial infection and the septic response in critical surgical illness. Sepsis, not infection, determines outcome.
TLDR
The differential roles of infection as a microbial phenomenon and sepsis as a host response were studied in 210 critically ill surgical patients, finding the magnitude of the host septic response is an important determinant of outcome in critical surgical illness.
Meta-analysis: Intravenous Immunoglobulin in Critically Ill Adult Patients with Sepsis
TLDR
A meta-analysis of 20 randomized trials that studied 2621 critically ill adult patients with sepsis found that treatment with polyclonal IVIG decreased the risk for death more than placebo or no intervention, and may be a useful adjuvant treatment.
...
...