The Lancet Infectious Diseases Commission
Sepsis: a roadmap for future research

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Summary

Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research.

Section snippets

Introduction: facing the challenge of sepsis

Patients with sepsis—a severe infection associated with organ dysfunction1—constitute a large proportion of the critically ill population and, although outcomes have improved,2 mortality remains higher than 25–30%, and even 40–50% when shock is present.3 No effective specific anti-sepsis treatments exist, therefore management of patients with sepsis relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate

An unresolved issue

An important difference exists between a definition that is used to identify an individual who has a specific disorder and a definition that is used for epidemiological purposes. The former definition might have therapeutic, prognostic, or sociological implications for the patient and will need to be pragmatic and easy to apply. By contrast, an epidemiological definition will often be used for clinical trials or for public health surveillance reasons and will need to be as robust and rigorous

The global epidemiology of sepsis

Sepsis is both one of the best known yet most poorly understood medical disorders. First recognised by Hippocrates, sepsis can be described as the state in which a host mounts an inflammatory response to an invading pathogen with poor results. The lay definition states that sepsis is a life-threatening disorder that arises when the body's response to an infection injures its own tissues and organs. Sepsis leads to shock, multiple organ failure, and death, especially if not recognised early and

Diagnostic microbiology

Diagnostic microbiology stands at the epicentre of the tests for sepsis in patients. Nowadays, microbiological studies for the detection of bacteria or fungi in blood, body fluids, or relevant tissues continue to rely for the most part on conventional culture-based systems, which remain the gold standard. Blood cultures are positive in 30–40% of patients with severe sepsis and septic shock.123 In most instances bloodstream infections are intermittent and the circulating microbial loads are low,

Molecular targets and experimental therapies for sepsis

Conventional management principles with timely administration of intravenous fluids, oxygen, and antimicrobials combined with so-called source control, drainage of infectious foci, and advanced organ support in an intensive-care setting have reduced the overall mortality of severe sepsis to historically low rates (<20%).2, 7 Regrettably, long-term outcomes suggest that substantial residual morbidity and excess mortality risks persist for survivors after initial treatment for septic shock. The

Failure of clinical sepsis trials

As we have noted earlier, although the outcome of patients with sepsis has improved substantially in recent years,2, 51 this improvement in outcome has not been accomplished by any of the many adjuvant therapies tested in more than 100 phase 2 and phase 3 clinical sepsis trials.308, 309 Rather, the improved sepsis prognosis is probably mainly caused by an increased recognition and faster intervention by health-care services for cases of sepsis than was previously achieved, possibly due to

Sepsis: a call to action

In conceiving and writing this Commission, our intent has been two fold. The first was to describe the present status of what is one of those most challenging medical disorders in routine clinical practice, and the second, to identify those areas in which we think research is most crucial in driving forward transformational change. This second intent, what we have called the roadmap for the future, has informed this call to action (panel 2). We acknowledge that we have intentionally left

References (349)

  • S Bello et al.

    Tobacco smoking increases the risk for death from pneumococcal pneumonia

    Chest

    (2014)
  • CW Coelho et al.

    Exercise training prevents skeletal muscle damage in an experimental sepsis model

    Clinics (Sao Paulo)

    (2013)
  • H Zhu et al.

    Rac1 mediates sex difference in cardiac tumor necrosis factor-alpha expression via NADPH oxidase-ERK1/2/p38 MAPK pathway in endotoxemia

    J Mol Cell Cardiol

    (2009)
  • N Sharawy et al.

    Estradiol receptors agonists induced effects in rat intestinal microcirculation during sepsis

    Microvasc Res

    (2013)
  • A Agarwal et al.

    Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S

    Blood

    (2000)
  • MJ Newport et al.

    The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia

    Tuberculosis (Edinb)

    (2004)
  • Y Xue et al.

    Spread of an inactive form of caspase-12 in humans is due to recent positive selection

    Am J Hum Genet

    (2006)
  • KM Kaukonen et al.

    Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012

    JAMA

    (2014)
  • C Rhee et al.

    Regulatory mandates for sepsis care—reasons for caution

    N Engl J Med

    (2014)
  • JL Vincent et al.

    Circulatory shock

    N Engl J Med

    (2013)
  • E Rivers et al.

    Early goal-directed therapy in the treatment of severe sepsis and septic shock

    N Engl J Med

    (2001)
  • DM Yealy et al.

    A randomized trial of protocol-based care for early septic shock

    N Engl J Med

    (2014)
  • SL Peake et al.

    Goal-directed resuscitation for patients with early septic shock

    N Engl J Med

    (2014)
  • R Ferrer et al.

    Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study

    Am J Respir Crit Care Med

    (2009)
  • S Finfer et al.

    Intensive versus conventional glucose control in critically ill patients

    N Engl J Med

    (2009)
  • E Boonen et al.

    Reduced cortisol metabolism during critical illness

    N Engl J Med

    (2013)
  • RC Bone et al.

    Sepsis syndrome: a valid clinical entity

    Crit Care Med

    (1989)
  • American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis

    Crit Care Med

    (1992)
  • MM Levy et al.

    2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

    Crit Care Med

    (2003)
  • RA Balk

    Systemic inflammatory response syndrome (SIRS): where did it come from and is it still relevant today?

    Virulence

    (2014)
  • RP Dellinger et al.

    Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

    Intensive Care Med

    (2013)
  • DC Angus

    The search for effective therapy for sepsis: back to the drawing board?

    JAMA

    (2011)
  • J Cohen

    The immunopathogenesis of sepsis

    Nature

    (2002)
  • A Dyson et al.

    Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting?

    Crit Care Med

    (2009)
  • AS Cross et al.

    Choice of bacteria in animal models of sepsis

    Infect Immun

    (1993)
  • J Seok et al.

    Genomic responses in mouse models poorly mimic human inflammatory diseases

    Proc Natl Acad Sci USA

    (2013)
  • TW Rice et al.

    A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis

    Crit Care Med

    (2010)
  • MC Reade et al.

    The clinical research enterprise in critical care: what's right, what's wrong, and what's ahead?

    Crit Care Med

    (2009)
  • A Kumar et al.

    Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

    Crit Care Med

    (2006)
  • J Carlet et al.

    Sepsis: time to reconsider the concept

    Crit Care Med

    (2008)
  • DC Angus et al.

    Severe sepsis and septic shock

    N Engl J Med

    (2013)
  • S Rehberg et al.

    Role of selective V1a receptor agonism in ovine septic shock

    Crit Care Med

    (2011)
  • RG Wunderink et al.

    Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial

    Am J Respir Crit Care Med

    (2011)
  • DP Stephens et al.

    Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock

    Crit Care Med

    (2008)
  • HR Wong et al.

    Developing a clinically feasible personalized medicine approach to pediatric septic shock

    Am J Respir Crit Care Med

    (2015)
  • K Reinhart et al.

    Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

    Crit Care Med

    (2001)
  • JL Vincent et al.

    A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation

    Crit Care Med

    (2013)
  • SM Opal et al.

    The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?

    Crit Care Med

    (2014)
  • JC Marshall et al.

    Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum

    Crit Care Med

    (2005)
  • CJ Czura

    “Merinoff symposium 2010: sepsis”-speaking with one voice

    Mol Med

    (2011)
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