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  • Review Article
  • Published:

Such stuff as dreams are made on: mediator-directed therapy in sepsis

Nature Reviews Drug Discovery volume 2, pages 391–405 (2003)Cite this article

Key Points

  • Sepsis generates estimated costs of >US $16 billion annually in the United States alone, and causes >200,000 deaths per year. However, despite considerable efforts, only one novel therapy has achieved regulatory approval in the past two decades.

  • If sepsis is defined conceptually as the clinical syndrome that results from the host response to invasive infection, then potential sepsis therapies can be categorized as those that target the inciting infection, those that are directed against the response of the host and those that treat the clinical sequelae of this process. Trials of each of these types of therapy are described.

  • Possible reasons for the lack of success of most potential sepsis therapies are discussed, including: absence or loss of the agent's biological activity; inappropriate dose, duration or timing of therapy; heterogeneity of the target population; and limitations of outcome measures.

  • A rational, sequential approach to the evaluation of novel therapies in sepsis is put forward.

Abstract

Sepsis, a life-threatening disorder that arises through the body's response to infection, is the leading cause of death and disability for patients in an intensive care unit. Advances in the understanding of the complex biological processes responsible for the clinical syndrome have led to the identification of many promising new therapeutic targets, including bacterial toxins, host-derived mediators, and downstream processes such as coagulation and the endocrine response. Diverse therapies directed against these targets have shown dramatic effects in animal models; however, in humans, their impact has been frustratingly modest, and only one agent — recombinant activated protein C — has achieved regulatory approval. 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.

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Figure 1: Activation of an innate immune response to invading microorganisms.
Figure 2: Randomized clinical trials evaluating the neutralization of endotoxin by an antibody.
Figure 3: Randomized trials of the neutralization of tumour necrosis factor with a monoclonal antibody.
Figure 4: Biosynthesis of lipid mediators of sepsis.
Figure 5: The coagulation cascade in sepsis.

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  1. Department of Surgery and the Interdepartmental Division of Critical Care Medicine, University of Toronto, Eaton North 9-234, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, Ontario, Canada

    John C. Marshall

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BPI

IFN-γ

LBP

PLA2G2A

TFPI

TLR4

TNFR1

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FURTHER INFORMATION

Encyclopedia of Life Sciences

Septicaemic shock

Glossary

MENINOGOCOCCAEMIA

An uncommon, but fulminant, infection with substantial mortality and morbidity in the form of tissue necrosis leading to the loss of digits and even limbs.

APACHE II SCORES

A composite measure of acute severity of illness, including variables reflecting acute (A) physiology (P), age (A) and chronic health evaluation (CHE).

ISOFORMS OF NOS

Constitutively expressed nitric oxide synthase is present in endothelial cells, neurons, and hepatocytes. An inducible form of the enzyme is also present in cells of the innate immune system; its expression is upregulated by endotoxin and pro-inflammatory cytokines.

ZYMOGEN

A proenzyme. Requires enzymatic activation to exert its own effects.

TNM STRATIFICATION SYSTEM

The TNM (tumours, nodes, metastasis) system, widely used in cancer clinical trials, characterizes patients by variables that not only correlate with prognosis, but also reflect a differential potential of response to therapy.

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Marshall, J. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2, 391–405 (2003). https://doi.org/10.1038/nrd1084

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