The Emperor Has No Clothes? Searching for Dysregulation in Sepsis

The core conception of sepsis—that it is a dysregulated state—is a powerful and durable idea that has inspired decades of research. But is it true that the body’s response to sepsis is dysregulated? To answer that question, this review surveyed the history of trials of experimental sepsis treatments targeting the host response. Sepsis survival is not improved by blocking one or many immune pathways. Similarly, sepsis is resistant to treatment by normalizing one or many physiologic parameters simultaneously. The vast majority of interventions are either ineffective or harmful. With this track record of failure, it is time to consider the alternative hypothesis—regulation instead of dysregulation—and the possibility that sepsis traits are often functional, and that some physiologic alterations in sepsis do more good than harm, while others are neutral. This review discusses the implications of this perspective for the future of sepsis research.