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  • Sepsis represents a transition from an appropriate, regulated immune response to a dysregulated response, resulting in organ damage and illness.

  • The response to pathogens is complex, with multiple built-in layers of redundancy, making it difficult to identify inividual pathways as either etiology or therapeutic target.

  • The inflammatory response to pathogens can be understood as a three-legged stool, involving (1) the pro-inflammatory response intended to clear pathogens; (2) the anti-inflammatory response to prevent injury to the host by the inflammatory response; (3) the pro-resolving response which focuses on repairing damage done by the host response to the pathogen or the pathogen itself; when any leg of this response is disrupted, the host develops sepsis.

  • The future of sepsis treatment depends on understanding the immunophenotype of each patient, both in terms of their various immune responses as well as in the context of the pathogen and site of infection.


Mortality due to severe sepsis remains at 20% to 30%, in spite of an aggressive campaign over the last 20 years aimed at improving outcomes through bundling of evidence-based therapies.1–3 In an effort to improve research into and care of this devastating disease, sepsis has been recently redefined as “life-threatening organ dysfunction caused by a dysregulated host response to infection.”4 This redefinition is informative: it acknowledges that sepsis is essentially an immune-mediated disease triggered by infection, and it moves beyond the prior definition of sepsis (clinical suspicion of infection coupled with several non-specific clinical criteria, termed systemic inflammatory response syndrome, or SIRS, Table 67-1). Clinically, “life-threatening organ dysfunction” is easily measured using the well-validated Sequential Organ Failure Assessment (SOFA) score, which incorporates objective measures of respiratory, hepatic, renal, cardiac, neurologic, and coagulation function.4 However, defining the “dysregulated host response to infection” is much more challenging and requires an understanding of the appropriate, “regulated” host response to infection, which itself remains incompletely understood.

TABLE 67-1SIRS Criteria

In their article “Sepsis and Scientific Revolutions,” Artenstein and colleagues use Kuhn’s The Structure of Scientific Revolutions paradigm to argue that sepsis is a “state in which complex biologic systems and inherent variability in interdependent physiologic responses frustrate a mechanistic approach.”5 By extension, a “linear, fix-what-is-broken strategy” of early antibiotics, bundled care, source control, or targeting specific pathways will only result in incremental improvements. Truly improving the care of the septic patient will require nothing short of a “scientific revolution,” wherein a “crisis of thought” occurs, triggered by “anomalous findings that cannot be explained by the scientific community’s shared views.” The crisis of thought in sepsis arises from ...

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