Opinion
Special issue: Sepsis
Why have clinical trials in sepsis failed?

https://doi.org/10.1016/j.molmed.2014.01.007Get rights and content

Highlights

  • The biology of sepsis is complex and not specific to infection.

  • Clinical criteria do not adequately delineate patients who will benefit from specific therapies.

  • Stratification systems are needed to guide optimal treatment decisions.

  • Success in developing new treatments will necessitate new collaborative research models.

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.

Section snippets

The landscape of sepsis clinical trials

The first clinical trial of the sepsis hypothesis, that the endogenous inflammatory response of the host determines the outcome of life-threatening infection, was published in 1976 [1]. In a study of 172 patients with septic shock, William Schumer reported that administration of large doses of methylprednisolone could reduce mortality from 39% to 11%. Forty years later, although the use of high dose steroids has been largely abandoned, controversy continues regarding the efficacy of lower

Sepsis and the biology of innate immunity

The work of Pasteur and others in the nineteenth century established the critical role of exogenous microorganisms in the pathogenesis of infection, and created the basic architecture of the germ theory of disease. The consequences have been transformative. Annual mortality from infectious disease in the USA declined from 800 cases per 100 000 in 1900 to approximately 70 cases per 100 000 a century later [6]. Strikingly, however, the most impressive declines reflected public health measures such

The study population

The entry criteria for most clinical trials targeting host- or microbial-derived mediators of a systemic inflammatory response are those of sepsis syndrome [4], or a closely related constellation of clinical manifestations known as the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, or septic shock [17]. Elizabeth Ziegler and colleagues reported in 1982 that administration of a polyclonal serum neutralizing endotoxin could reduce mortality rates in patients with

Defining the challenge

The challenge of reorienting our approach to the study of modulating the host response in critical illness is a daunting one. It requires a fundamental reassessment of the assumptions of the concept of sepsis, building on contemporary understanding of biology and the complexity of innate immunity and adaptive immunity. It also requires a critical reconsideration of the prevailing research paradigm, from the role of preclinical models to the sources and impact of heterogeneity in clinical

Rethinking the research model

The shortcomings of the prevalent approach to the identification, development, and testing of novel therapies of sepsis are many. How to address them is less clear; elements of a possible approach are articulated here.

Concluding remarks

Defined as a clinical syndrome resulting from the adverse consequences of the host response to infection, sepsis is arguably the leading cause of preventable death in the world today; four of the World Health Organization's top ten causes of global mortality result from sepsis. It can be conservatively estimated that upwards of $10 billion has been spent with the objective of developing effective adjuvant treatments to meet this unmet need. Yet, with the failure of a recent confirmatory trial

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