The inability to develop an anti-inflammatory agent with clear clinical benefit for patients with sepsis has led to the concept that sepsis is much more complex and variable than previously believed, making for a very elusive target. Natanson et al
35 wrote in 1994, “Perhaps our therapeutic premise has been flawed: Attempting to block the harmful effects of inflammatory mediators may not produce a net benefit [in patients with sepsis] because it may also compromise host defense and ultimately worsen outcome.” Natanson et al
35 suggested that there is variability in the host response to infection, such as an excessive inflammatory response, immunocompetence, or immunocompromise. The concept of a compensatory anti-inflammatory response syndrome was developed by Bone et al,
39,47 who suggested that an initial intense inflammatory reaction occurs in individuals with sepsis, followed by an immunosuppressed state or downregulation of the immune response. This decrease in immune response, if not recovered, may result in death.
39,47 The findings of Natanson et al,
35 Bone et al,
39,47 and others demonstrate the complex, variable nature of sepsis. Sometimes it is referred to as the “sepsis syndrome” (
Figure 2).
Several mechanisms of immunosuppression in sepsis have been investigated. Among the research findings related to these mechanisms are the following: